Substituted derivatives of pyrido[3,2-e][1,4]thiazino[4,3-a]pyrazine and pyrido[3,2-e][1,4]oxazino[4,3-a]pyrazine

ABSTRACT

Disclosed are compounds of the following formula: 
                         
in which R 1 , R 2 , R 6 , R 7 , R 12 , X, and q are defined in the specification. Also disclosed are pharmaceutical compositions, kits, and articles of manufacture, which contain the compounds, methods and intermediates useful for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions related to PARP activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 13/041,200, filed Mar.4, 2011, now U.S. Pat. No. 8,124,606, which is a divisional of U.S. Ser.No. 12/691,668, filed Jan. 21, 2010, now U.S. Pat. No. 7,928,105, whichclaims the benefit of U.S. Provisional Applications No. 61/146,740,filed Jan. 23, 2009, and 61/228,879, filed Jul. 27, 2009, which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to compounds that may be used to inhibitPoly (ADP-ribose) Polymerase (PARP), as well as compositions of matter,kits and articles of manufacture comprising these compounds. Theinvention also relates to methods for inhibiting PARP and treatmentmethods using compounds according to the present invention. In addition,the invention relates to methods of making the compounds of the presentinvention, as well as intermediates useful in such methods.

The present invention relates to inhibitors of the enzymepoly(ADP-ribose)polymerase (PARP), previously known aspoly(ADP-ribose)synthase and poly(ADP-ribosyl)transferase. PARPconstitutes a super family of proteins containing PARP catalyticdomains. These proteins include PARP-1, PARP-2, PARP-3, vaultPARP andTiPARP. PARP-I consists of an amino (N)-terminal DNA-binding domain(DBD) containing two zinc fingers; an automodification domain; and acarboxy (C)-terminal catalytic domain.

PARP is a nuclear and cytoplasmic enzyme that cleaves NAD+ tonicotinamide and ADP-ribose to form long and branched ADP-ribosepolymers on target proteins, including topoisomerases, histones and PARPitself PARP has been implicated in several biological processes,including DNA repair, gene transcription, cell cycle progression(including proliferation and differentiation), cell death, chromatinfunctions, genomic (e.g., chromosomal) stability and telomere length.

Activation of PARP and the resultant formation of poly(ADP-ribose) canbe induced by DNA strand breaks after exposure to chemotherapy, ionizingradiation, oxygen free radicals, or nitric oxide (NO). Because thiscellular ADP-ribose transfer process is associated with the repair ofDNA strand breakage in response to DNA damage caused by radiotherapy orchemotherapy, it can contribute to the resistance that often develops tovarious types of cancer therapies. Consequently, inhibition of PARP isexpected to retard intracellular DNA repair and enhance the antitumoreffects of cancer therapies.

In addition, tankyrases (e.g., tankyrase-1 and tankyrase-2) which bindto the telomeric protein TRF-1, a negative regulator of telomere lengthmaintenance, have a catalytic domain that is homologous to PARP. It hasbeen proposed that telomere function in human cells is regulated bypoly(ADP-ribosyl)ation. As a consequence of regulation of telomeraseactivity by tankyrase, PARP inhibitors are expected to have utility asagents for use in cancer therapy (e.g., to shorten the life-span ofimmortal tumor cells) or as anti-aging therapeutics, since telomerelength is believed to be associated with cell senescence.

In addition, PARP modulation has been implicated in vascular andcardiovascular diseases, metabolic diseases, inflammatory diseases,reperfusion injuries, ischemic conditions, neurodegenerative diseasesand more.

There is a continued need to find new therapeutic agents to treat humandiseases. PARP is an especially attractive target for the discovery ofnew therapeutics due to its important role in cancers, vascular andcardiovascular diseases, metabolic diseases, inflammatory diseases,reperfusion injuries, ischemic conditions, neurodegenerative diseasesand other diseases.

SUMMARY OF THE INVENTION

The present invention relates to compounds that have activity forinhibiting PARP. The present invention also provides compositions,articles of manufacture and kits comprising these compounds. Inaddition, the invention relates to methods of making the compounds ofthe present invention, as well as intermediates useful in such methods.The compounds of the present invention show in vivo efficacy in animalmodels, increased cellular potentiation, strong and sustainedpharmacodynamic effects in tumours, and longer time-to-tumourprogression (TTP).

In one embodiment, a pharmaceutical composition is provided thatcomprises a PARP inhibitor according to the present invention as anactive ingredient. Pharmaceutical compositions according to theinvention may optionally comprise 0.001%-100% of one or more inhibitorsof this invention. These pharmaceutical compositions may be administeredor co-administered by a wide variety of routes, including for example,orally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, or intrathecally. The compositionsmay also be administered or co-administered in slow release dosageforms.

The invention is also directed to kits and other articles of manufacturefor treating disease states associated with PARP.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one PARP inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one PARP inhibitor of thepresent invention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

Also provided are methods for preparing compounds, compositions and kitsaccording to the present invention. For example, several syntheticschemes are provided herein for synthesizing compounds according to thepresent invention.

Also provided are methods for using compounds, compositions, kits andarticles of manufacture according to the present invention.

In one embodiment, the compounds, compositions, kits and articles ofmanufacture are used to inhibit PARP.

In another embodiment, the compounds, compositions, kits and articles ofmanufacture are used to treat a disease state for which PARP possessactivity that contributes to the pathology and/or symptomology of thedisease state.

In another embodiment, a compound according to the present invention isadministered to a subject wherein PARP activity within the subject isaltered, preferably reduced.

In another embodiment, a prodrug of a compound according to the presentinvention is administered to a subject that is converted to the compoundin vivo where it inhibits PARP.

In another embodiment, a method of inhibiting PARP is provided thatcomprises contacting a PARP with a compound according to the presentinvention.

In another embodiment, a method of inhibiting PARP is provided thatcomprises causing a compound according to the present invention to bepresent in a subject in order to inhibit PARP in vivo.

In another embodiment, a method of inhibiting a PARP is provided thatcomprises administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibits PARPin vivo. It is noted that the compounds of the present invention may bethe first or second compounds.

In another embodiment, a therapeutic method is provided that comprisesadministering a compound according to the present invention.

In another embodiment, a method is provided for treating a condition ina patient that is known to be mediated by PARP, or which is known to betreated by PARP inhibitors, the method comprising administering to thepatient a therapeutically effective amount of a compound according tothe present invention.

In another embodiment, a method is provided for treating a disease statefor which PARP possess activity that contributes to the pathology and/orsymptomology of the disease state, the method comprising: causing acompound according to the present invention to be present in a subjectin a therapeutically effective amount for the disease state.

In another embodiment, a method is provided for treating a disease statefor which PARP possess activity that contributes to the pathology and/orsymptomology of the disease state, the method comprising: administeringa first compound to a subject that is converted in vivo to a secondcompound such that the second compound is present in the subject in atherapeutically effective amount for the disease state. It is noted thatthe compounds of the present invention may be the first or secondcompounds.

In another embodiment, a method is provided for treating a disease statefor which PARP possess activity that contributes to the pathology and/orsymptomology of the disease state, the method comprising: administeringa compound according to the present invention to a subject such that thecompound is present in the subject in a therapeutically effective amountfor the disease state.

In another embodiment, a method is provided for using a compoundaccording to the present invention in order to manufacture a medicamentfor use in the treatment of a disease state that is known to be mediatedby PARP, or that is known to be treated by PARP inhibitors.

It is noted in regard to all of the above embodiments that the presentinvention is intended to encompass all pharmaceutically acceptableionized forms (e.g., salts) and solvates (e.g., hydrates) of thecompounds, regardless of whether such ionized forms and solvates arespecified since it is well known in the art to administer pharmaceuticalagents in an ionized or solvated form. It is also noted that unless aparticular stereochemistry is specified, recitation of a compound isintended to encompass all possible stereoisomers (e.g., enantiomers ordiastereomers depending on the number of chiral centers), independent ofwhether the compound is present as an individual isomer or a mixture ofisomers. Further, unless otherwise specified, recitation of a compoundis intended to encompass all possible resonance forms and tautomers.With regard to the claims, the language “compound comprising theformula,” “compound having the formula” and “compound of the formula” isintended to encompass the compound and all pharmaceutically acceptableionized forms and solvates, all possible stereoisomers, and all possibleresonance forms and tautomers unless otherwise specifically specified inthe particular claim.

It is further noted that prodrugs may also be administered which arealtered in vivo and become a compound according to the presentinvention. The various methods of using the compounds of the presentinvention are intended, regardless of whether prodrug delivery isspecified, to encompass the administration of a prodrug that isconverted in vivo to a compound according to the present invention. Itis also noted that certain compounds of the present invention may bealtered in vivo prior to inhibiting PARP and thus may themselves beprodrugs for another compound. Such prodrugs of another compound may ormay not themselves independently have PARP inhibitory activity.

Definitions

Unless otherwise stated, the following terms used in the specificationand claims shall have the following meanings for the purposes of thisapplication.

It is noted that, as used in the specification and the appended claims,the singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Further, definitions of standardchemistry terms may be found in reference works, including Carey andSundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.” Vols. A (2000) and B(2001), Plenum Press, New York. Also, unless otherwise indicated,conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology, within theskill of the art are employed.

“Alicyclic” means a moiety comprising a non-aromatic ring structure.Alicyclic moieties may be saturated or partially unsaturated with one,two or more double or triple bonds. Alicyclic moieties may alsooptionally comprise heteroatoms such as nitrogen, oxygen and sulfur. Thenitrogen atoms can be optionally quaternerized or oxidized and thesulfur atoms can be optionally oxidized. Examples of alicyclic moietiesinclude, but are not limited to moieties with (C₃₋₈) rings such ascyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one, two or more double or triple bonds.

“Alkenyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon double bond (—CR═CR′— or —CR═CR′R″, wherein R,R′ and R″ are each independently hydrogen or further substituents).Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl,hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and thelike. In particular embodiments, “alkenyl,” either alone or representedalong with another radical, can be a (C₂₋₂₀)alkenyl, a (C₂₋₁₅)alkenyl, a(C₂₋₁₀alkenyl, a (C₂₋₅)alkenyl or a (C₂₋₃)alkenyl. Alternatively,“alkenyl,” either alone or represented along with another radical, canbe a (C₂)alkenyl, a (C₃)alkenyl or a (C₄)alkenyl.

“Alkenylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon double bonds (—CR═CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkenylene include ethene-1,2-diyl, propene-1,3-diyl,methylene-1,1-diyl, and the like. In particular embodiments,“alkenylene,” either alone or represented along with another radical,can be a (C₂₋₂₀) alkenylene, a (C₂₋₁₅) alkenylene, a (C₂₋₁₀ alkenylene,a (C₂₋₅) alkenylene or a (C₂₋₃) alkenylene. Alternatively, “alkenylene,”either alone or represented along with another radical, can be a (C₂)alkenylene, a (C₃) alkenylene or a (C₄) alkenylene.

“Alkoxy” means an oxygen moiety having a further alkyl substituent. Thealkoxy groups of the present invention can be optionally substituted.

“Alkyl” represented by itself means a straight or branched, saturated orunsaturated, aliphatic radical having a chain of carbon atoms,optionally with one or more of the carbon atoms being replaced withoxygen (See “oxaalkyl”), a carbonyl group (See “oxoalkyl”), sulfur (See“thioalkyl”), and/or nitrogen (See “azaalkyl”). (C_(X))alkyl and(C_(X-Y))alkyl are typically used where X and Y indicate the number ofcarbon atoms in the chain. For example, (C₁₋₆)alkyl includes alkyls thathave a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl,1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl,ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented alongwith another radical (e.g., as in arylalkyl, heteroarylalkyl and thelike) means a straight or branched, saturated or unsaturated aliphaticdivalent radical having the number of atoms indicated or when no atomsare indicated means a bond (e.g., (C₆₋₁₀)aryl(C₁₋₃)alkyl includes,benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl,2-pyridinylmethyl and the like). In particular embodiments, “alkyl,”either alone or represented along with another radical, can be a(C₁₋₂₀)alkyl, a (C₁₋₁₅)alkyl, a (C₁₋₁₀)alkyl, a (C₁₋₅)alkyl or a(C₁₋₃)alkyl. Alternatively, “alkyl,” either alone or represented alongwith another radical, can be a (C₁)alkyl, a (C₂)alkyl or a (C₃)alkyl.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic, divalent radical. (C_(X))alkyleneand (C_(X-Y))alkylene are typically used where X and Y indicate thenumber of carbon atoms in the chain. For example, (C₁₋₆)alkyleneincludes methylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene(—CH₂CH₂CH₂—), tetramethylene (—CH₂CH₂CH₂CH₂—) 2-butenylene(—CH₂CH═CHCH₂—), 2-methyltetramethylene (—CH₂CH(CH₃)CH₂CH₂—),pentamethylene (—CH₂CH₂CH₂CH₂CH₂—) and the like. In particularembodiments, “alkylene,” either alone or represented along with anotherradical, can be a (C₁₋₂₀)alkylene, a (C₁₋₁₅)alkylene, a (C₁₋₁₀)alkylene,a (C₁₋₅)alkylene or a (C₁₋₃)alkylene. Alternatively, “alkylene,” eitheralone or represented along with another radical, can be a (C₁)alkylene,a (C₂)alkylene or a (C₃)alkylene.

“Alkylidene” means a straight or branched, saturated or unsaturated,aliphatic radical connected to the parent molecule by a double bond.(C_(X))alkylidene and (C_(X-Y))alkylidene are typically used where X andY indicate the number of carbon atoms in the chain. For example,(C₁₋₆)alkylidene includes methylene (═CH₂), ethylidene (═CHCH₃),isopropylidene (═C(CH₃)₂), propylidene (═CHCH₂CH₃), allylidene(═CH—CH═CH₂), and the like. In particular embodiments, “alkylidene,”either alone or represented along with another radical, can be a(C₁₋₂₀)alkylidene, a (C₁₋₁₅)alkylidene, a (C₁₋₁₀)alkylidene, a(C₁₋₅)alkylidene or a (C₁₋₃)alkylidene. Alternatively, “alkylidene,”either alone or represented along with another radical, can be a(C₁)alkylidene, a (C₂)alkylidene or a (C₃)alkylidene.

“Alkynyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon triple bond (—C≡C— or —C≡CR, wherein R ishydrogen or a further substituent). Examples of alkynyl include ethynyl,propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. In particularembodiments, “alkynyl,” either alone or represented along with anotherradical, can be a (C₂₋₂₀)alkynyl, a (C₂₋₁₅)alkynyl, a (C₂₋₁₀)alkynyl, a(C₂₋₅)alkynyl or a (C₂₋₃)alkynyl. Alternatively, “alkynyl,” either aloneor represented along with another radical, can be a (C₂)alkynyl, a(C₃)alkynyl or a (C₄)alkynyl.

“Alkynylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon triple bonds (—CR≡CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkynylene include ethyne-1,2-diyl, propyne-1,3-diyl, and the like. Inparticular embodiments, “alkynylene,” either alone or represented alongwith another radical, can be a (C₂₋₂₀) alkynylene, a (C₂₋₁₅) alkynylene,a (C₂₋₁₀) alkynylene, a (C₂₋₅) alkynylene or a (C₂₋₃) alkynylene.Alternatively, “alkynylene,” either alone or represented along withanother radical, can be a (C₂) alkynylene, a (C₃) alkynylene or a (C₄)alkynylene.

“Amido” means the radical —C(═O)—NR—, —C(═O)—NRR′, —NR—C(═O)— and/or—NR—C(═O)R′, wherein each R and R′ are independently hydrogen or afurther substituent.

“Amino” means a nitrogen moiety having two further substituents where,for example, a hydrogen or carbon atom is attached to the nitrogen. Forexample, representative amino groups include —NH₂, —NHCH₃, —N(CH₃)₂,—NH((C₁₋₁₀)alkyl), —N((C₁₋₁₀)alkyl)₂, —NH(aryl), —NH(heteroaryl),—N(aryl)₂, —N(heteroaryl)₂, and the like. Optionally, the twosubstituents together with the nitrogen may also form a ring. Unlessindicated otherwise, the compounds of the invention containing aminomoieties may include protected derivatives thereof. Suitable protectinggroups for amino moieties include acetyl, tert-butoxycarbonyl,benzyloxycarbonyl, and the like.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2. An aromatic ringmay be such that the ring atoms are only carbon atoms or may includecarbon and non-carbon atoms (See “heteroaryl”).

“Aryl” means a monocyclic or polycyclic ring assembly wherein each ringis aromatic or when fused with one or more rings forms an aromatic ringassembly. If one or more ring atoms is not carbon (e.g., N, S), the arylis a heteroaryl. (C_(X))aryl and (C_(X-Y))aryl are typically used whereX and Y indicate the number of carbon atoms in the ring. In particularembodiments, “aryl,” either alone or represented along with anotherradical, can be a (C₃₋₁₄)aryl, a (C₃₋₁₀)aryl, a (C₃₋₇)aryl, a(C₈₋₁₀)aryl or a (C₅₋₇)aryl. Alternatively, “aryl,” either alone orrepresented along with another radical, can be a (C₅)aryl, a (C₆)aryl, a(C₇)aryl, a (C₈)aryl, a (C₉)aryl or a (C₁₀)aryl.

“Azaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with substitutedor unsubstituted nitrogen atoms (—NR— or —NRR′, wherein R and R′ areeach independently hydrogen or further substituents). For example, a(C₁₋₁₀)azaalkyl refers to a chain comprising between 1 and 10 carbonsand one or more nitrogen atoms.

“Bicycloalkyl” means a saturated or partially unsaturated fused, spiroor bridged bicyclic ring assembly. In particular embodiments,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₄₋₁₅)bicycloalkyl, a (C₄₋₁₀)bicycloalkyl, a(C₆₋₁₀)bicycloalkyl or a (C₈₋₁₀)bicycloalkyl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloalkyl, a (C₉)bicycloalkyl or a (C₁₀)bicycloalkyl.

“Bicycloaryl” means a fused, spiro or bridged bicyclic ring assemblywherein at least one of the rings comprising the assembly is aromatic.(C_(X))bicycloaryl and (C_(X-Y))bicycloaryl are typically used where Xand Y indicate the number of carbon atoms in the bicyclic ring assemblyand directly attached to the ring. In particular embodiments,“bicycloaryl,” either alone or represented along with another radical,can be a (a (C₄₋₁₅)bicycloaryl, a (C₄₋₁₀)bicycloaryl, a(C₆₋₁₀)bicycloaryl or a (C₈₋₁₀)bicycloaryl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloaryl, a (C₉)bicycloaryl or a (C₁₀)bicycloaryl.

“Bridging ring” and “bridged ring” as used herein refer to a ring thatis bonded to another ring to form a compound having a bicyclic orpolycyclic structure where two ring atoms that are common to both ringsare not directly bound to each other. Non-exclusive examples of commoncompounds having a bridging ring include borneol, norbornane,7-oxabicyclo[2.2.1]heptane, and the like. One or both rings of thebicyclic system may also comprise heteroatoms.

“Carbamoyl” means the radical —OC(O)NRR′, wherein R and R′ are eachindependently hydrogen or further substituents.

“Carbocycle” means a ring consisting of carbon atoms.

“Carbonyl” means the radical —C(═O)— and/or —C(═O)R, wherein R ishydrogen or a further substituent. It is noted that the carbonyl radicalmay be further substituted with a variety of substituents to formdifferent carbonyl groups including acids, acid halides, aldehydes,amides, esters, and ketones.

“Carboxy” means the radical —C(═O)—O— and/or —C(═O)—OR, wherein R ishydrogen or a further substituent. It is noted that compounds of theinvention containing carboxy moieties may include protected derivativesthereof, i.e., where the oxygen is substituted with a protecting group.Suitable protecting groups for carboxy moieties include benzyl,tert-butyl, and the like.

“Cyano” means the radical —CN.

“Cycloalkyl” means a non-aromatic, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyl and(C_(X-Y))cycloalkyl are typically used where X and Y indicate the numberof carbon atoms in the ring assembly. For example, (C₃₋₄₀)cycloalkylincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl,decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,2-oxobicyclo[2.2.1]hept-1-yl, and the like. In particular embodiments,“cycloalkyl,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkyl, a (C₃₋₄₀)cycloalkyl, a (C₃₋₇)cycloalkyl, a(C₈₋₄₀)cycloalkyl or a (C₅₋₇)cycloalkyl. Alternatively, “cycloalkyl,”either alone or represented along with another radical, can be a(C₅)cycloalkyl, a (C₆)cycloalkyl, a (C₇)cycloalkyl, a (C₈)cycloalkyl., a(C₉)cycloalkyl or a (C₁₀)cycloalkyl.

“Cycloalkylene” means a divalent, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyleneand (C_(X-Y))cycloalkylene are typically used where X and Y indicate thenumber of carbon atoms in the ring assembly. In particular embodiments,“cycloalkylene,” either alone or represented along with another radical,can be a (C₃₋₄₄)cycloalkylene, a (C₃₋₄₀)cycloalkylene, a(C₃₋₇)cycloalkylene, a (C₈₋₄₀)cycloalkylene or a (C₅₋₇)cycloalkylene.Alternatively, “cycloalkylene,” either alone or represented along withanother radical, can be a (C₅)cycloalkylene, a (C₆)cycloalkylene, a(C₇)cycloalkylene, a (C₈)cycloalkylene., a (C₉)cycloalkylene or a(C₁₀)cycloalkylene.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Fused ring” as used herein refers to a ring that is bonded to anotherring to form a compound having a bicyclic structure where the ring atomsthat are common to both rings are directly bound to each other.Non-exclusive examples of common fused rings include decalin,naphthalene, anthracene, phenanthrene, indole, furan, benzofuran,quinoline, and the like. Compounds having fused ring systems may besaturated, partially saturated, carbocyclics, heterocyclics, aromatics,heteroaromatics, and the like.

“Halo” means fluoro, chloro, bromo or iodo.

“Heteroalkyl” means alkyl, as defined in this application, provided thatone or more of the atoms within the alkyl chain is a heteroatom. Inparticular embodiments, “heteroalkyl,” either alone or represented alongwith another radical, can be a hetero(C₁₋₂₀)alkyl, a hetero(C₁₋₁₅)alkyl,a hetero(C₁₋₁₀)alkyl, a hetero(C₁₋₅)alkyl, a hetero(C₁₋₃)alkyl or ahetero(C₁₋₂)alkyl. Alternatively, “heteroalkyl,” either alone orrepresented along with another radical, can be a hetero(C₁)alkyl, ahetero(C₂)alkyl or a hetero(C₃)alkyl.

“Heteroaryl” means a monocyclic, bicyclic or polycyclic aromatic groupwherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. Monocyclic heteroaryl groups include, but are notlimited to, cyclic aromatic groups having five or six ring atoms,wherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. The nitrogen atoms can be optionally quaternerized andthe sulfur atoms can be optionally oxidized. Heteroaryl groups of thisinvention include, but are not limited to, those derived from furan,imidazole, isothiazole, isoxazole, oxadiazole, oxazole,1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole.“Heteroaryl” also includes, but is not limited to, bicyclic or tricyclicrings, wherein the heteroaryl ring is fused to one or two ringsindependently selected from the group consisting of an aryl ring, acycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroarylor heterocycloalkyl ring. These bicyclic or tricyclic heteroarylsinclude, but are not limited to, those derived from benzo[b]furan,benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline,thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine,indolizine, imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine,quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole,indoline, benzoxazole, benzopyrazole, benzothiazole,imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,carbazole, acridine, phenazine, phenothiazene, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and2(1H)-pyridinone. The bicyclic or tricyclic heteroaryl rings can beattached to the parent molecule through either the heteroaryl groupitself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl groupto which it is fused. The heteroaryl groups of this invention can besubstituted or unsubstituted. In particular embodiments, “heteroaryl,”either alone or represented along with another radical, can be ahetero(C₁₋₁₃)aryl, a hetero(C₂₋₁₃)aryl, a hetero(C₂₋₆)aryl, ahetero(C₃₋₉)aryl or a hetero(C₅₋₉)aryl. Alternatively, “heteroaryl,”either alone or represented along with another radical, can be ahetero(C₃)aryl, a hetero(C₄)aryl, a hetero(C₅)aryl, a hetero(C₆)aryl., ahetero(C₇)aryl, a hetero(C₈)aryl or a hetero(C₉)aryl.

“Heteroatom” refers to an atom that is not a carbon atom. Particularexamples of heteroatoms include, but are not limited to, nitrogen,oxygen, and sulfur.

“Heteroatom moiety” includes a moiety where the atom by which the moietyis attached is not a carbon. Examples of heteroatom moieties include—NR—, —N⁺(O⁻)═, —O—, —S— or —S(O)₂—, wherein R is hydrogen or a furthersubstituent.

“Heterobicycloalkyl” means bicycloalkyl, as defined in this application,provided that one or more of the atoms within the ring is a heteroatom.For example hetero(C₉₋₁₂)bicycloalkyl as used in this applicationincludes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl,2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and thelike. In particular embodiments, “heterobicycloalkyl,” either alone orrepresented along with another radical, can be ahetero(C₁₋₁₄)bicycloalkyl, a hetero(C₄₋₁₄)bicycloalkyl, ahetero(C₄₋₉)bicycloalkyl or a hetero(C₅₋₉)bicycloalkyl. Alternatively,“heterobicycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloalkyl, hetero(C₆)bicycloalkyl,hetero(C₇)bicycloalkyl, hetero(C₈)bicycloalkyl or ahetero(C₉)bicycloalkyl.

“Heterobicycloaryl” means bicycloaryl, as defined in this application,provided that one or more of the atoms within the ring is a heteroatom.For example, hetero(C₄₋₁₂)bicycloaryl as used in this applicationincludes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl,tetrahydroisoquinolinyl, and the like. In particular embodiments,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₄)bicycloaryl, a hetero(C₄₋₁₄)bicycloaryl,a hetero(C₄₋₉)bicycloarylor a hetero(C₅₋₉)bicycloaryl. Alternatively,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloaryl, hetero(C₆)bicycloaryl,hetero(C₇)bicycloaryl, hetero(C₈)bicycloaryl or a hetero(C₉)bicycloaryl.

“Heterocycloalkyl” means cycloalkyl, as defined in this application,provided that one or more of the atoms forming the ring is a heteroatomselected, independently from N, O, or S, Non-exclusive examples ofheterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl,pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl,1,3-dioxanyl, 1,4-dioxanyl and the like. In particular embodiments,“heterocycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₃)cycloalkyl, a hetero(C₁₋₉)cycloalkyl, ahetero(C₁₋₆)cycloalkyl, a hetero(C₅₋₉)cycloalkyl or ahetero(C₂₋₆)cycloalkyl. Alternatively, “heterocycloalkyl,” either aloneor represented along with another radical, can be ahetero(C₂)cycloalkyl, a hetero(C₃)cycloalkyl, a hetero(C₄)cycloalkyl, ahetero(C₅)cycloalkyl, a hetero(C₆)cycloalkyl, hetero(C₇)cycloalkyl,hetero(C₈)cycloalkyl or a hetero(C₉)cycloalkyl.

“Heterocycloalkylene” means cycloalkylene, as defined in thisapplication, provided that one or more of the ring member carbon atomsis replaced by a heteroatom. In particular embodiments,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₃)cycloalkylene, ahetero(C₁₋₉)cycloalkylene, a hetero(C₁₋₆)cycloalkylene, ahetero(C₅₋₉)cycloalkylene or a hetero(C₂₋₆)cycloalkylene. Alternatively,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₂)cycloalkylene, a hetero(C₃)cycloalkylene, ahetero(C₄)cycloalkylene, a hetero(C₅)cycloalkylene, ahetero(C₆)cycloalkylene, hetero(C₇)cycloalkylene,hetero(C₈)cycloalkylene or a hetero(C₉)cycloalkylene.

“Hydroxy” means the radical —OH.

“IC₅₀” means the molar concentration of an inhibitor that produces 50%inhibition of the target enzyme.

“Imino” means the radical —CR(═NR′) and/or —C(═NR′)—, wherein R and R′are each independently hydrogen or a further substituent.

“Isomers” means compounds having identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers.” A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter.” A compound with one chiral center has two enantiomeric forms ofopposite chirality. A mixture of the two enantiomeric forms is termed a“racemic mixture.” A compound that has more than one chiral center has2^(n-1) enantiomeric pairs, where n is the number of chiral centers.Compounds with more than one chiral center may exist as ether anindividual diastereomer or as a mixture of diastereomers, termed a“diastereomeric mixture.” When one chiral center is present astereoisomer may be characterized by the absolute configuration of thatchiral center. Absolute configuration refers to the arrangement in spaceof the substituents attached to the chiral center. Enantiomers arecharacterized by the absolute configuration of their chiral centers anddescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog.Conventions for stereochemical nomenclature, methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (e.g., see “Advanced Organic Chemistry”, 4thedition, March, Jerry, John Wiley & Sons, New York, 1992).

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under reaction (e.g., alkylating) conditions.Examples of leaving groups include, but are not limited to, halo (e.g.,F, Cl, Br and I), alkyl (e.g., methyl and ethyl) and sulfonyloxy (e.g.,mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosyloxy),thiomethyl, thienyloxy, dihalophosphinoyloxy, tetrahalophosphoxy,benzyloxy, isopropyloxy, acyloxy, and the like.

“Moiety providing X atom separation” and “linker providing X atomseparation” between two other moieties mean that the chain of atomsdirectly linking the two other moieties is X atoms in length. When X isgiven as a range (e.g., X₁-X₂), then the chain of atoms is at least X₁and not more than X₂ atoms in length. It is understood that the chain ofatoms can be formed from a combination of atoms including, for example,carbon, nitrogen, sulfur and oxygen atoms. Further, each atom canoptionally be bound to one or more substituents, as valencies allow. Inaddition, the chain of atoms can form part of a ring. Accordingly, inone embodiment, a moiety providing X atom separation between two othermoieties (R and R′) can be represented by R-(L)_(x)-R′ where each L isindependently selected from the group consisting of CR″R′″, NR′″, O, S,CO, CS, C═NR′″″, SO, SO₂, and the like, where any two or more of R″,R′″, R″″ and R can be taken together to form a substituted orunsubstituted ring.

“Nitro” means the radical —NO₂.

“Oxaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with oxygen atoms(—O— or —OR, wherein R is hydrogen or a further substituent). Forexample, an oxa(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more oxygen atoms.

“Oxoalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with carbonylgroups (—C(═O)— or —C(═O)—R, wherein R is hydrogen or a furthersubstituent). The carbonyl group may be an aldehyde, ketone, ester,amide, acid, or acid halide. For example, an oxo(C₁₋₁₀)alkyl refers to achain comprising between 1 and 10 carbon atoms and one or more carbonylgroups.

“Oxy” means the radical —O— or —OR, wherein R is hydrogen or a furthersubstituent. Accordingly, it is noted that the oxy radical may befurther substituted with a variety of substituents to form different oxygroups including hydroxy, alkoxy, aryloxy, heteroaryloxy or carbonyloxy.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as aceticacid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonicacid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Polycyclic ring” includes bicyclic and multi-cyclic rings. Theindividual rings comprising the polycyclic ring can be fused, spiro orbridging rings.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have activity with respect to a given targetprotein. For example, a compound comprising a hydroxy group may beadministered as an ester that is converted by hydrolysis in vivo to thehydroxy compound. Suitable esters that may be converted in vivo intohydroxy compounds include acetates, citrates, lactates, phosphates,tartrates, malonates, oxalates, salicylates, propionates, succinates,fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates,isethionates, di-p-toluoyltartrates, methanesulfonates,ethanesulfonates, benzenesulfonates, p-toluenesulfonates,cyclohexylsulfamates, quinates, esters of amino acids, and the like.Similarly, a compound comprising an amine group may be administered asan amide that is converted by hydrolysis in vivo to the amine compound.

“Protected derivatives” means derivatives of inhibitors in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of inhibitors or in themselvesmay be active as inhibitors. A comprehensive list of suitable protectinggroups can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

“Ring” and “ring assembly” means a carbocyclic or a heterocyclic systemand includes aromatic and non-aromatic systems. The system can bemonocyclic, bicyclic or polycyclic. In addition, for bicyclic andpolycyclic systems, the individual rings comprising the polycyclic ringcan be fused, spiro or bridging rings.

“Subject” and “patient” include humans, non-human mammals (e.g., dogs,cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like)and non-mammals (e.g., birds, and the like).

“Substituent convertible to hydrogen in vivo” means any group that isconvertible to a hydrogen atom by enzymological or chemical meansincluding, but not limited to, hydrolysis and hydrogenolysis. Examplesinclude hydrolyzable groups, such as acyl groups, groups having anoxycarbonyl group, amino acid residues, peptide residues,o-nitrophenylsulfenyl, trimethylsilyl, tetrahydro-pyranyl,diphenylphosphinyl, and the like. Examples of acyl groups includeformyl, acetyl, trifluoroacetyl, and the like. Examples of groups havingan oxycarbonyl group include ethoxycarbonyl, t-butoxycarbonyl[(CH₃)₃C—OCO—], benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,vinyloxycarbonyl, β-(p-toluenesulfonyl)ethoxycarbonyl, and the like.Examples of suitable amino acid residues include amino acid residues perse and amino acid residues that are protected with a protecting group.Suitable amino acid residues include, but are not limited to, residuesof Gly (glycine), Ala (alanine; CH₃CH(NH₂)CO—), Arg (arginine), Asn(asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid),H is (histidine), Ile (isoleucine), Leu (leucine;(CH₃)₂CHCH₂CH(NH₂)CO—), Lys (lysine), Met (methionine), Phe(phenylalanine), Pro (proline), Ser (serine), Thr (threonine), Trp(tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse(homoserine), 4-Hyp (4-hydroxyproline), 5-Hyl (5-hydroxylysine), Orn(ornithine) and (β-Ala. Examples of suitable protecting groups includethose typically employed in peptide synthesis, including acyl groups(such as formyl and acetyl), arylmethyloxycarbonyl groups (such asbenzyloxycarbonyl and p-nitrobenzyloxycarbonyl), t-butoxycarbonyl groups[(CH₃)₃C—OCO—], and the like. Suitable peptide residues include peptideresidues comprising two to five, and optionally two to three, of theaforesaid amino acid residues. Examples of such peptide residuesinclude, but are not limited to, residues of such peptides as Ala-Ala[CH₃CH(NH₂)CO—NHCH(CH₃)CO—], Gly-Phe, Nva-Nva, Ala-Phe, Gly-Gly,Gly-Gly-Gly, Ala-Met, Met-Met, Leu-Met and Ala-Leu. The residues ofthese amino acids or peptides can be present in stereochemicalconfigurations of the D-form, the L-form or mixtures thereof. Inaddition, the amino acid or peptide residue may have an asymmetriccarbon atom. Examples of suitable amino acid residues having anasymmetric carbon atom include residues of Ala, Leu, Phe, Trp, Nva, Val,Met, Ser, Lys, Thr and Tyr. Peptide residues having an asymmetric carbonatom include peptide residues having one or more constituent amino acidresidues having an asymmetric carbon atom. Examples of suitable aminoacid protecting groups include those typically employed in peptidesynthesis, including acyl groups (such as formyl and acetyl),arylmethyloxycarbonyl groups (such as benzyloxycarbonyl andp-nitrobenzyloxycarbonyl), t-butoxycarbonyl groups [(CH₃)₃C—OCO—], andthe like. Other examples of substituents “convertible to hydrogen invivo” include reductively eliminable hydrogenolyzable groups. Examplesof suitable reductively eliminable hydrogenolyzable groups include, butare not limited to, arylsulfonyl groups (such as o-toluenesulfonyl);methyl groups substituted with phenyl or benzyloxy (such as benzyl,trityl and benzyloxymethyl); arylmethoxycarbonyl groups (such asbenzyloxycarbonyl and o-methoxy-benzyloxycarbonyl); andhalogenoethoxycarbonyl groups (such as β, β, β-trichloroethoxycarbonyland β-iodoethoxycarbonyl).

“Substituted or unsubstituted” means that a given moiety may consist ofonly hydrogen substituents through available valencies (unsubstituted)or may further comprise one or more non-hydrogen substituents throughavailable valencies (substituted) that are not otherwise specified bythe name of the given moiety. For example, isopropyl is an example of anethylene moiety that is substituted by —CH₃. In general, a non-hydrogensubstituent may be any substituent that may be bound to an atom of thegiven moiety that is specified to be substituted. Examples ofsubstituents include, but are not limited to, aldehyde, alicyclic,aliphatic, (C₁₋₁₀)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl,aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl,carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo,heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl,heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl,and oxoalkyl moieties, each of which may optionally also be substitutedor unsubstituted. In one particular embodiment, examples of substituentsinclude, but are not limited to, hydrogen, halo, nitro, cyano, thio,oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,(C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl. In addition, the substituent is itselfoptionally substituted by a further substituent. In one particularembodiment, examples of the further substituent include, but are notlimited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl.

“Sulfinyl” means the radical —SO— and/or —SO—R, wherein R is hydrogen ora further substituent. It is noted that the sulfinyl radical may befurther substituted with a variety of substituents to form differentsulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters,and sulfoxides.

“Sulfonyl” means the radical —SO₂— and/or —SO₂—R, wherein R is hydrogenor a further substituent. It is noted that the sulfonyl radical may befurther substituted with a variety of substituents to form differentsulfonyl groups including sulfonic acids, sulfonamides, sulfonateesters, and sulfones.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thio” denotes replacement of an oxygen by a sulfur and includes, but isnot limited to, —SR, —S— and ═S containing groups.

“Thioalkyl” means an alkyl, as defined above, except where one or moreof the carbon atoms forming the alkyl chain are replaced with sulfuratoms (—S— or —S—R, wherein R is hydrogen or a further substituent). Forexample, a thio(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more sulfur atoms.

“Thiocarbonyl” means the radical —C(═S)— and/or —C(═S)—R, wherein R ishydrogen or a further substituent. It is noted that the thiocarbonylradical may be further substituted with a variety of substituents toform different thiocarbonyl groups including thioacids, thioamides,thioesters, and thioketones.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

(1) preventing the disease from occurring in an animal which may bepredisposed to the disease but does not yet experience or display thepathology or symptomatology of the disease,

(2) inhibiting the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,arresting further development of the pathology and/or symptomatology),or

(3) ameliorating the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,reversing the pathology and/or symptomatology).

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, a C₁alkyl indicates that there is one carbon atom but does not indicate whatthe substituents on the carbon atom are. Hence, a (C₁)alkyl comprisesmethyl (i.e., —CH₃) as well as —CRR′R″ where R, R′, and R″ may eachindependently be hydrogen or a further substituent where the atomattached to the carbon is a heteroatom or cyano. Hence, CF₃, CH₂OH andCH₂CN, for example, are all (C₁)alkyls. Similarly, terms such asalkylamino and the like comprise dialkylamino and the like.

A compound having a formula that is represented with a dashed bond isintended to include the formulae optionally having zero, one or moredouble bonds, as exemplified and shown below:

In addition, atoms making up the compounds of the present invention areintended to include all isotopic forms of such atoms. Isotopes, as usedherein, include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude ¹³C and ¹⁴C.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that may be used to inhibitPARP. The present invention also relates to pharmaceutical compositions,kits and articles of manufacture comprising such compounds. In addition,the present invention relates to methods and intermediates useful formaking the compounds. Further, the present invention relates to methodsof using said compounds. It is noted that the compounds of the presentinvention may also possess activity for other members of the sameprotein family and thus may be used to address disease states associatedwith these other family members.

PARP Inhibitors

In one of its aspects, the present invention relates to compounds thatare useful as PARP inhibitors. In one embodiment, PARP inhibitors of thepresent invention comprise:

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein

-   -   t is selected from the group consisting of 1 or 2;    -   X is selected from the group consisting of O, S and NR₈;    -   R₁ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        amino(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; or R₁ is -L₁-R₁₃;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₁₃ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        betero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen,        carbonyloxy, (C₁₋₁₀)alkoxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        betero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; or R₃ has the formula -L₂-R₁₈;    -   L₂ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₁₈ and the ring to which L₂ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur;    -   R₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   or any two of R₃, R₄ and R₅ are taken together to form a        substituted or unsubstituted ring;    -   R₆ is selected from the group consisting of hydrogen,        carbonyloxy, carbonyl, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        betero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₈ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        betero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; or R₁₃ has the formula:

-   -   R₁₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₉ and R₂₀ are each independently selected from the group        consisting of hydrogen, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₀ and R₂₀ are taken together        to form a substituted or unsubstituted ring.

In one variation of the above embodiment, the compound is not: (i)3-methylpyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one; (ii)3-methoxypyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one; (iii)2-(3-chloro-6-oxo-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-5(6H)-yl)-N-o-tolylacetamide;(iv)2-(3-chloro-6-oxo-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-5(6H)-yl)-N-(3-(trifluoromethyl)phenyl)acetamide;(v)5-oxo-3-(2-trifluoromethyl-benzyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline-8-carboxylicacid isopropylamide; (vi)3-(5-Fluoro-2-trifluoromethyl-benzoyl)-5-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline-8-carboxylicacid phenylamide; (vii)5-oxo-3-(2-trifluoromethyl-benzoyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline-8-carboxylicacid pentylamide; or (viii)3-(5-Fluoro-2-trifluoromethyl-benzoyl)-5-oxo-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline-8-carboxylicacid butylamide.

In a further embodiment, PARP inhibitors of the present inventioncomprise:

In another embodiment, PARP inhibitors of the present inventioncomprise:

In still another embodiment, PARP inhibitors of the present inventioncomprise:

In yet another embodiment, PARP inhibitors of the present inventioncomprise:

In a further embodiment, PARP inhibitors of the present inventioncomprise:

In still a further embodiment, PARP inhibitors of the present inventioncomprise:

In yet a further embodiment, PARP inhibitors of the present inventioncomprise:

In another embodiment, PARP inhibitors of the present inventioncomprise:

In still another embodiment, PARP inhibitors of the present inventioncomprise:

In yet another embodiment, PARP inhibitors of the present inventioncomprise:

In a further embodiment, PARP inhibitors of the present inventioncomprise:

In still a further embodiment, PARP inhibitors of the present inventioncomprise:

In yet a further embodiment, PARP inhibitors of the present inventioncomprise:

In another embodiment, PARP inhibitors of the present inventioncomprise:

In still another embodiment, PARP inhibitors of the present inventioncomprise:

In yet another embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   p is selected from the group consisting of 0, 1, 2, 3, 4 and 5;        and    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   p is selected from the group consisting of 0, 1, 2, 3, 4 and 5;        and    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   p is selected from the group consisting of 0, 1, 2, 3, 4 and 5;        and    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   p is selected from the group consisting of 0, 1, 2, 3, 4 and 5;        and    -   R₉ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   u is selected from the group consisting of 0, 1, 2, 3, 4, 5 and        6; and    -   R₃₁ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero (C₃₋₁₂)cyclo alkyl, (C₉₋₁₂)bicyclo        alkyl, hetero (C₃₋₁₂)bicyclo alkyl, (C₄₋₁₂)aryl,        hetero(C₄₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, PARP inhibitors of the present inventioncomprise:

In a further embodiment, PARP inhibitors of the present inventioncomprise:

In yet a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   u is selected from the group consisting of 0, 1, 2, 3, 4, 5 and        6; and    -   R₃₁ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero(C₃₋₁₂)cycloalkyl,        (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,        hetero(C₄₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still another embodiment, PARP inhibitors of the present inventioncomprise:

In yet another embodiment, PARP inhibitors of the present inventioncomprise:

In another embodiment, PARP inhibitors of the present inventioncomprise:

In a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   n is selected from the group consisting of 0, 1 and 2; and    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7 and 8; and    -   R₁₁ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In another embodiment, PARP inhibitors of the present inventioncomprise:

In still another embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7 and 8; and    -   R₁₁ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet another embodiment, PARP inhibitors of the present inventioncomprise:

In yet a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7 and 8; and    -   R₁₁ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In another embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7 and 8; and    -   R₁₁ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still another embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   q is selected from the group consisting of 0, 1, 2, 3, 4, 5 and        6; and    -   R₁₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet another embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   q is selected from the group consisting of 0, 1, 2, 3, 4, 5 and        6; and    -   R₁₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   q is selected from the group consisting of 0, 1, 2, 3, 4, 5 and        6; and    -   R₁₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   q is selected from the group consisting of 0, 1, 2, 3, 4, 5 and        6; and    -   R₁₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   q is selected from the group consisting of 0, 1, 2, 3, 4, 5 and        6; and    -   R₁₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In another embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   q is selected from the group consisting of 0, 1, 2, 3, 4, 5 and        6; and    -   R₁₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still another embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   q is selected from the group consisting of 0, 1, 2, 3, 4, 5 and        6; and    -   R₁₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further embodiment, PARP inhibitors of the present inventioncomprise:

-   -   wherein    -   v is selected from the group consisting of 0, 1, 2, 3 and 4; and    -   R₃₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In one variation of each of the above embodiments and variations, X isO.

In another variation of each of the above embodiments and variations,

-   -   R₁ is -L₁-R₁₃;    -   L₁ is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between R₁₃ and the ring to which L₁ is attached,        wherein the atoms of the linker providing the separation are        selected from the group consisting of carbon, oxygen, nitrogen,        and sulfur; and    -   R₁₃ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations,

-   -   L₁ is absent or a linker selected from the group consisting of        —(CR₁₄R₁₅)_(r)—, —CO—, —CS—, —C(═NR₁₆)—, —NR₁₇—, —O—, —S—, —SO—,        —SO₂— and combinations thereof;    -   r is selected from the group consisting of 1, 2 and 3;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero(C₃₋₁₂)cycloalkyl,        (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,        hetero(C₄₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   R₁₆ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero(C₃₋₁₂)cycloalkyl,        (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,        hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and    -   R₁₇ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero(C₃₋₁₂)cycloalkyl,        (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,        hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet another variation of each of the above embodiments andvariations,

-   -   L₁ is —CR₁₄R₁₅—;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further variation of each of the above embodiments and variations,L₁ is —CH₂—.

In another variation of each of the above embodiments and variations, L₁is —CF₂—. In still a further variation of each of the above embodimentsand variations, L₁ is —NR₁—. In yet a further variation of each of theabove embodiments and variations, L₁ is —O—.

In yet another variation of each of the above embodiments andvariations, R₂ is hydrogen. In a further variation of each of the aboveembodiments and variations, R₂ is halo. In still a further variation ofeach of the above embodiments and variations, R₂ is a substituted orunsubstituted (C₁₋₃) alkyl.

In still another variation of each of the above embodiments andvariations, R₃ is a substituted or unsubstituted (C₁₋₃)alkyl. In yetanother variation of each of the above embodiments and variations, R₃ ismethyl. In a further variation of each of the above embodiments andvariations, R₃ is ethyl. In still a further variation of each of theabove embodiments and variations, R₃ is propyl. In yet a furthervariation of each of the above embodiments and variations, R₃ isisopropyl. In another variation of each of the above embodiments andvariations, R₃ is a substituted or unsubstituted aryl(C₁₋₆)alkyl. Instill another variation of each of the above embodiments and variations,R₃ is a substituted or unsubstituted benzyl.

In yet another variation of each of the above embodiments andvariations, R₃ has the formula -L₂-R₁₈, wherein L₂ is absent or a linkerproviding 1, 2, 3, 4, 5 or 6 atom separation between R₁₈ and the ring towhich L₂ is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; and R₁₈ is selected from the group consisting ofhydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.

In a further variation of each of the above embodiments and variations,

-   -   L₂ is absent or a linker selected from the group consisting of        —(CR₁₄R₁₅)_(r)—, —CO—, —CS—, —C(═NR₁₆)—, —NR₁₇—, —O—, —S—, —SO—,        —SO₂— and combinations thereof;    -   r is selected from the group consisting of 1, 2 and 3;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        betero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        betero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₁₆ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        betero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₇ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still a further variation of each of the above embodiments andvariations,

-   -   L₂ is —CR₁₄R₁₅—;    -   R₁₄ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₅ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet a further variation of each of the above embodiments andvariations, L₂ is —CH₂—.

In still another variation of each of the above embodiments andvariations, R₄ is a substituted or unsubstituted (C₁₋₃)alkyl. In yetanother variation of each of the above embodiments and variations, R₄ ismethyl. In a further variation of each of the above embodiments andvariations, R₄ is hydrogen.

In still a further variation of each of the above embodiments andvariations, R₃ and R₄, together with the atoms to which they areattached, are taken to form a substituted or unsubstituted 3, 4, 5, 6, 7or 8 membered ring. In yet a further variation of each of the aboveembodiments and variations, R₃ and R₄, together with the atoms to whichthey are attached, are taken to form a substituted or unsubstituted 3,4, 5, 6, 7 or 8 membered heterocycloalkyl ring. In another variation ofeach of the above embodiments and variations, R₃ and R₄, together withthe atoms to which they are attached, are taken to form a substituted orunsubstituted 3, 4, 5, 6, 7 or 8 membered heterocycloaryl ring.

In yet another variation of each of the above embodiments andvariations, R₅ is hydrogen. In a further variation of each of the aboveembodiments and variations, R₅ is halo. In still a further variation ofeach of the above embodiments and variations, R₅ is a substituted orunsubstituted (C₁₋₃) alkyl.

In yet another variation of each of the above embodiments andvariations, R₆ is hydrogen. In still a further variation of each of theabove embodiments and variations, R₆ is a substituted or unsubstituted(C₁₋₃) alkyl.

In yet another variation of each of the above embodiments andvariations, R₇ is hydrogen. In a further variation of each of the aboveembodiments and variations, R₇ is halo. In still a further variation ofeach of the above embodiments and variations, R₇ is a substituted orunsubstituted (C₁₋₃) alkyl.

In still a further variation of each of the above embodiments andvariations, R₈ is hydrogen. In yet a further variation of each of theabove embodiments and variations, R₈ is a substituted or unsubstituted(C₁₋₃)alkyl.

In yet a further variation of each of the above embodiments andvariations, R₉ is hydrogen. In another variation of each of the aboveembodiments and variations, R₉ is halo. In still another variation ofeach of the above embodiments and variations, R₉ is a substituted orunsubstituted (C₁₋₃)alkyl.

In yet a further variation of each of the above embodiments andvariations, R₁₀ is hydrogen. In another variation of each of the aboveembodiments and variations, R₁₀ is halo. In still another variation ofeach of the above embodiments and variations, R₁₀ is a substituted orunsubstituted (C₁₋₃)alkyl.

In yet a further variation of each of the above embodiments andvariations, R₁₁ is hydrogen. In another variation of each of the aboveembodiments and variations, R₁₁ is halo. In still another variation ofeach of the above embodiments and variations, R₁₁ is a substituted orunsubstituted (C₁₋₃)alkyl.

In yet a further variation of each of the above embodiments andvariations, R₁₂ is hydrogen. In another variation of each of the aboveembodiments and variations, R₁₂ is halo. In still another variation ofeach of the above embodiments and variations, R₁₂ is a substituted orunsubstituted (C₁₋₃)alkyl.

In a further variation of each of the above embodiments and variations,R₁₃ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted. In anothervariation of each of the above embodiments and variations, R₁₃ isselected from the group consisting of hetero(C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, hetero(C₁₋₁₀)aryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still a further variation of each of the above embodiments andvariations, R₁₃ has the formula:

-   -   wherein    -   R₁₉ and R₂₀ are each independently selected from the group        consisting of hydrogen, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₁₉ and R₂₀ are taken together        to form a substituted or unsubstituted ring.

In yet a further variation of each of the above embodiments andvariations, R₁₃ is a substituted or unsubstituted piperazinyl.

In another variation of each of the above embodiments and variations,R₁₃ has the formula

-   -   wherein    -   s is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7 and 8;    -   R₂₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In another variation of each of the above embodiments and variations,R₁₃ has the formula:

-   -   wherein    -   R₂₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero (C₃₋₁₂)cyclo alkyl, (C₉₋₁₂)bicyclo        alkyl, hetero (C₃₋₁₂)bicyclo alkyl, (C₄₋₁₂)aryl,        hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, R₁₃ has the formula:

-   -   wherein    -   R₂₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero(C₃₋₁₂)cycloalkyl,        (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,        hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet another variation of each of the above embodiments andvariations, R₁₃ has the formula:

-   -   wherein    -   s is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,        7 and 8;    -   R₂₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₈ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, R₁₃ is a substituted or unsubstituted piperidinyl.

In yet another variation of each of the above embodiments andvariations, R₁₃ has the formula:

-   -   wherein    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further variation of each of the above embodiments and variations,R₁₃ is a substituted or unsubstituted 1,2,3,6-tetrahydropyridinyl.

In still a further variation of each of the above embodiments andvariations, R₁₃ has the formula:

-   -   wherein    -   R₂₂ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet a further variation of each of the above embodiments andvariations, R₁₃ is a substituted or unsubstituted 3-oxo-piperazinyl.

In another variation of each of the above embodiments and variations,R₁₃ has the formula:

-   -   wherein    -   Y is selected from the group consisting of O and S; and    -   R₂₁ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, Y is O.

In yet another variation of each of the above embodiments andvariations, R₁₄ is hydrogen. In a further variation of each of the aboveembodiments and variations, R₁₄ is halo. In still a further variation ofeach of the above embodiments and variations, R₁₄ is a substituted orunsubstituted (C₁₋₃) alkyl.

In yet another variation of each of the above embodiments andvariations, R₁₅ is hydrogen. In a further variation of each of the aboveembodiments and variations, R₁₅ is halo. In still a further variation ofeach of the above embodiments and variations, R₁₅ is a substituted orunsubstituted (C₁₋₃) alkyl.

In yet a further variation of each of the above embodiments andvariations, R₁₆ is hydrogen. In still another variation of each of theabove embodiments and variations, R₁₆ is a substituted or unsubstituted(C₁₋₃)alkyl.

In another variation of each of the above embodiments and variations,R₁₇ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted. In yet a further variation of each of theabove embodiments and variations, R₁₇ is hydrogen. In still anothervariation of each of the above embodiments and variations, R₁₇ is asubstituted or unsubstituted (C₁₋₃)alkyl.

In another variation of each of the above embodiments and variations,R₁₈ is a substituted or unsubstituted phenyl.

In a further variation of each of the above embodiments and variations,R₁₉ is hydrogen. In still a further variation of each of the aboveembodiments and variations, R₁₉ is a substituted or unsubstituted(C₁₋₃)alkyl.

In another variation of each of the above embodiments and variations,R₂₀ is hydrogen. In still a further variation of each of the aboveembodiments and variations, R₂₀ is a substituted or unsubstituted(C₁₋₃)alkyl.

In a further variation of each of the above embodiments and variations,R₁₉ and R₂₀ are taken together to form a substituted or unsubstitutedring. In still a further variation of each of the above embodiments andvariations, R₁₉ and R₂₀ are taken together to form a substituted orunsubstituted hetero(C₃₋₁₂)cycloalkyl. In yet a further variation ofeach of the above embodiments and variations, R₁₉ and R₂₀ are takentogether to form a substituted or unsubstitutedhetero(C₃₋₁₂)bicycloalkyl. In another variation of each of the aboveembodiments and variations, R₁₉ and R₂₀ are taken together to form asubstituted or unsubstituted hetero(C₁₋₁₀)aryl. In still anothervariation of each of the above embodiments and variations, R₁₉ and R₂₀are taken together to form a substituted or unsubstitutedhetero(C₄₋₁₂)bicycloaryl.

In still another variation of each of the above embodiments andvariations, R₂₁ is selected from the group consisting of(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted. In yet another variation of each of the above embodimentsand variations, R₂₁ is a substituted or unsubstituted phenyl. In afurther variation of each of the above embodiments and variations, R₂₁is a substituted or unsubstituted 4-chlorophenyl. In still a furthervariation of each of the above embodiments and variations, R₂₁ is asubstituted or unsubstituted pyridinyl.

In still another variation of each of the above embodiments andvariations, R₂₁ has the formula:

-   -   wherein    -   λ is selected from the group consisting of 0, 1, 2, 3 and 4;    -   each R₂₆ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,        (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,        oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero(C₃₋₁₂)cycloalkyl,        (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,        hetero(C₄₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet another variation of each of the above embodiments andvariations, R₂₁ has the formula:

-   -   wherein    -   R_(26a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        betero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero(C₃₋₁₂)cycloalkyl,        (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,        hetero(C₄₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In a further variation of each of the above embodiments and variations,R₂₁ has the formula:

-   -   wherein    -   R_(26b) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        betero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero(C₃₋₁₂)cycloalkyl,        (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,        hetero(C₄₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In still a further variation of each of the above embodiments andvariations, R₂₁ has the formula:

-   -   wherein    -   R_(26a) and R_(26b) are each independently selected from the        group consisting of hydrogen, halo, nitro, cyano, thio, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxo alkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero(C₃₋₁₂)cycloalkyl,        (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,        hetero(C₄₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet a further variation of each of the above embodiments andvariations, R₂₁ has the formula:

-   -   wherein    -   R₂₃ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero(C₃₋₁₂)cycloalkyl,        (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,        hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another variation of each of the above embodiments and variations,R₂₁ has the formula:

-   -   wherein    -   R₂₃ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, R₂₁ is substituted with a substituent selected from thegroup consisting of halo, cyano and a substituted or unsubstitutedcarbonyl. In yet another variation of each of the above embodiments andvariations, R₂₁ is substituted with a substituent having the formula—C(═O)—R₂₄, wherein R₂₄ is selected from the group consisting ofhydrogen, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido,amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.

In another variation of each of the above embodiments and variations,R₂₁ has the formula:

-   -   wherein    -   v is selected from the group consisting of 0, 1, 2 and 3;    -   each R₃₂ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,        (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,        oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, R₂₁ has the formula:

-   -   wherein    -   v is selected from the group consisting of 0, 1, 2 and 3;    -   each R₃₂ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,        (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,        oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further variation of each of the above embodiments and variations,R₂₂ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted. In still afurther variation of each of the above embodiments and variations, R₂₂is a substituted or unsubstituted phenyl. In yet a further variation ofeach of the above embodiments and variations, R₂₂ is a substituted orunsubstituted 4-chlorophenyl. In another variation of each of the aboveembodiments and variations, R₂₂ is a substituted or unsubstitutedpyridinyl.

In still another variation of each of the above embodiments andvariations, R₂₂ has the formula:

-   -   wherein    -   R₂₃ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl, hetero(C₃₋₁₂)cycloalkyl,        (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,        hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet another variation of each of the above embodiments andvariations, R₂₂ has the formula:

-   -   wherein    -   R₂₃ is selected from the group consisting of hydrogen, hydroxy,        carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further variation of each of the above embodiments and variations,R₂₂ is substituted with a substituent selected from the group consistingof halo, cyano and a substituted or unsubstituted carbonyl. In still afurther variation of each of the above embodiments and variations, R₂₂is substituted with a substituent having the formula —C(═O)—R₂₄, whereinR₂₄ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₄₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted.

In a further variation of each of the above embodiments and variations,R₂₂ has the formula:

-   -   wherein    -   λ is selected from the group consisting of 0, 1, 2, 3 and 4;    -   each R₂₆ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,        (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,        oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still a further variation of each of the above embodiments andvariations, R₂₂ has the formula:

-   -   wherein    -   R_(26a) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet a further variation of each of the above embodiments andvariations, R₂₂ has the formula:

-   -   wherein    -   R_(26b) is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        betero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        betero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        betero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In another variation of each of the above embodiments and variations,R₂₂ has the formula:

-   -   wherein    -   R_(26a) and R_(26b) are each independently selected from the        group consisting of hydrogen, halo, nitro, cyano, thio, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amido, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In another variation of each of the above embodiments and variations,R₂₂ has the formula:

-   -   wherein    -   v is selected from the group consisting of 0, 1, 2 and 3;    -   each R₃₂ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,        (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,        oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, R₂₂ has the formula:

-   -   wherein    -   v is selected from the group consisting of 0, 1, 2 and 3;    -   each R₃₂ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,        (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,        oxycarbonyl, amido, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₂₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        amido, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,        (C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero (C₃₋₁₂)cyclo alkyl, (C₉₋₁₂)bicyclo        alkyl, hetero (C₃₋₁₂)bicyclo alkyl, (C₄₋₁₂)aryl,        hetero(C₄₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet a further variation of each of the above embodiments andvariations, R₂₃ is a substituted or unsubstituted (C₁₋₃)alkyl. Inanother variation of each of the above embodiments and variations, R₂₃is a substituted or unsubstituted (C₃₋₆)cycloalkyl. In still anothervariation of each of the above embodiments and variations, R₂₃ ismethyl, ethyl, propyl, isopropyl or cyclopropyl.

In yet a further variation of each of the above embodiments andvariations, R₂₄ is hydroxyl. In another variation of each of the aboveembodiments and variations, R₂₄ is a substituted or unsubstituted(C₁₋₃)alkoxy. In still another variation of each of the aboveembodiments and variations, R₂₄ is a substituted or unsubstituted(C₁₋₃)alkylamino. In yet another variation of each of the aboveembodiments and variations, R₂₄ is hydrogen. In still a furthervariation of each of the above embodiments and variations, R₂₄ is asubstituted or unsubstituted (C₁₋₃) alkyl.

In another variation of each of the above embodiments and variations,R₂₆ is hydrogen. In still another variation of each of the aboveembodiments and variations, R₂₆ is halo. In yet another variation ofeach of the above embodiments and variations, R₂₆ is a substituted orunsubstituted (C₁₋₃) alkyl. In a further variation of each of the aboveembodiments and variations, R₂₆ is a substituted or unsubstituted(C₁₋₃)alkoxy. In still a further variation of each of the aboveembodiments and variations, R₂₆ is fluoro, chloro, methyl or methoxy.

In another variation of each of the above embodiments and variations,R_(26a) is hydrogen. In still another variation of each of the aboveembodiments and variations, R_(26a) is halo. In yet another variation ofeach of the above embodiments and variations, R_(26a) is a substitutedor unsubstituted (C₁₋₃) alkyl. In a further variation of each of theabove embodiments and variations, R_(26a) is a substituted orunsubstituted (C₁₋₃)alkoxy. In still a further variation of each of theabove embodiments and variations, R_(26a) is fluoro, chloro, methyl ormethoxy.

In another variation of each of the above embodiments and variations,R_(26b) is hydrogen. In still another variation of each of the aboveembodiments and variations, R_(26b) is halo. In yet another variation ofeach of the above embodiments and variations, R_(26b) is a substitutedor unsubstituted (C₁₋₃) alkyl. In a further variation of each of theabove embodiments and variations, R_(26b) is a substituted orunsubstituted (C₁₋₃)alkoxy. In still a further variation of each of theabove embodiments and variations, R_(26b) is fluoro, chloro, methyl ormethoxy.

In another variation of each of the above embodiments and variations,R₂₇ is —CO—NH—R₂₃; and R₂₃ is selected from the group consisting ofhydrogen, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.

In still another variation of each of the above embodiments andvariations, R₂₇ is —CO—O—R₂₃; and R₂₃ is selected from the groupconsisting of hydrogen, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.

In yet another variation of each of the above embodiments andvariations, R₂₇ is —SO₂—O—R₂₃; and R₂₃ is selected from the groupconsisting of hydrogen, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.

In a further variation of each of the above embodiments and variations,R₂₇ is —CO—NR₂₉R₃₀; and R₂₉ and R₃₀ are each independently selected fromthe group consisting of hydrogen, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₂₉ and R₃₀ are taken together to form a substitutedor unsubstituted ring.

In still a further variation of each of the above embodiments andvariations, R₂₇ is cyano. In another variation of each of the aboveembodiments and variations, R₂₇ is halo. In yet a further variation ofeach of the above embodiments and variations, R₂₇ is chloro. In anothervariation of each of the above embodiments and variations, R₂₇ isfluoro.

In still another variation of each of the above embodiments andvariations, R₂₈ is hydrogen. In yet another variation of each of theabove embodiments and variations, R₂₈ is halo. In a further variation ofeach of the above embodiments and variations, R₂₈ is a substituted orunsubstituted (C₁₋₃) alkyl. In a further variation of each of the aboveembodiments and variations, R₂₈ is a substituted or unsubstituted (C₁₋₃)alkoxy. In still a further variation of each of the above embodimentsand variations, R₂₈ is a substituted or unsubstituted amino. In yet afurther variation of each of the above embodiments and variations, R₂₈is thio.

In still a further variation of each of the above embodiments andvariations, R₂₉ is hydrogen. In yet a further variation of each of theabove embodiments and variations, R₂₉ is a substituted or unsubstituted(C₁₋₃) alkyl.

In another variation of each of the above embodiments and variations,R₃₀ is hydrogen. In still another variation of each of the aboveembodiments and variations, R₃₀ is a substituted or unsubstituted (C₁₋₃)alkyl.

In yet another variation of each of the above embodiments andvariations, R₃₁ is hydrogen. In a further variation of each of the aboveembodiments and variations, R₃₁ is halo. In still a further variation ofeach of the above embodiments and variations, R₃₁ is a substituted orunsubstituted (C₁₋₃) alkyl.

In yet another variation of each of the above embodiments andvariations, R₃₂ is hydrogen. In a further variation of each of the aboveembodiments and variations, R₃₂ is halo. In still a further variation ofeach of the above embodiments and variations, R₃₂ is a substituted orunsubstituted (C₁₋₃) alkyl.

In another variation of each of the above embodiments and variations,

-   -   R₁ is -L₁-R₁₃;    -   L₁ is —CH₂—;    -   R₁₃ has the formula:

-   -   R₂₁ has the formula:

-   -   λ is selected from the group consisting of 0, 1 and 2;    -   each R₂₆ is independently selected from the group consisting of        hydrogen, halo, (C₁₋₃) alkyl and (C₁₋₃)alkoxy;    -   R₂₇ is —CO—NH—R₂₃; and    -   R₂₃ is selected from the group consisting of (C₁₋₃)alkyl and        (C₃₋₆)cycloalkyl.

In still another variation of each of the above embodiments andvariations, n is 0. In yet another variation of each of the aboveembodiments and variations, n is 1. In a further variation of each ofthe above embodiments and variations, 1 is 0. In still a furthervariation of each of the above embodiments and variations, 1 is 1. Inyet a further variation of each of the above embodiments and variations,1 is 2. In a further variation of each of the above embodiments andvariations, m is 0. In still a further variation of each of the aboveembodiments and variations, m is 1. In yet a further variation of eachof the above embodiments and variations, p is 0. In another variation ofeach of the above embodiments and variations, p is 1. In still anothervariation of each of the above embodiments and variations, q is 0. Inyet another variation of each of the above embodiments and variations, qis 1. In still a further variation of each of the above embodiments andvariations, r is 1. In yet a further variation of each of the aboveembodiments and variations, r is 2. In a further variation of each ofthe above embodiments and variations, s is 0. In still a furthervariation of each of the above embodiments and variations, s is 1. Inyet a further variation of each of the above embodiments and variations,is 2. In another variation of each of the above embodiments andvariations, t is 1. In still another variation of each of the aboveembodiments and variations, u is 0. In yet another variation of each ofthe above embodiments and variations, u is 1. In a further variation ofeach of the above embodiments and variations, v is 0. In still a furthervariation of each of the above embodiments and variations, v is 1.

In another of its aspects, the present invention relates to methods ofmaking compounds that are useful as PARP inhibitors.

In still another of its aspects, the present invention relates tointermediates that are useful in making PARP inhibitors.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt, biohydrolyzable ester,biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate orprodrug thereof. For example, the compound optionally comprises asubstituent that is convertible in vivo to a different substituent suchas hydrogen.

It is further noted that the compound may be present as a mixture ofstereoisomers, or the compound may be present as a single stereoisomer.

In another of its aspects, there is provided a pharmaceuticalcomposition comprising a compound according to any one of the aboveembodiments and variations; and one or more pharmaceutically acceptableexcipients. In one particular variation, the composition is a solidformulation adapted for oral administration. In another particularvariation, the composition is a liquid formulation adapted for oraladministration. In yet another particular variation, the composition isa tablet. In still another particular variation, the composition is aliquid formulation adapted for parenteral administration.

The present invention also provides a pharmaceutical compositioncomprising a compound according to any one of the above embodiments andvariations, wherein the composition is adapted for administration by aroute selected from the group consisting of orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, and intrathecally.

In yet another of its aspects, there is provided a kit comprising acompound of any one of the above embodiments and variations; andinstructions which comprise one or more forms of information selectedfrom the group consisting of indicating a disease state for which thecomposition is to be administered, storage information for thecomposition, dosing information and instructions regarding how toadminister the composition. In one particular variation, the kitcomprises the compound in a multiple dose form.

In still another of its aspects, there is provided an article ofmanufacture comprising a compound of any one of the above embodimentsand variations; and packaging materials. In one variation, the packagingmaterial comprises a container for housing the compound. In oneparticular variation, the container comprises a label indicating one ormore members of the group consisting of a disease state for which thecompound is to be administered, storage information, dosing informationand/or instructions regarding how to administer the compound. In anothervariation, the article of manufacture comprises the compound in amultiple dose form.

In a further of its aspects, there is provided a therapeutic methodcomprising administering a compound of any one of the above embodimentsand variations to a subject.

In another of its aspects, there is provided a method of inhibiting PARPcomprising contacting PARP with a compound of any one of the aboveembodiments and variations.

In yet another of its aspects, there is provided a method of inhibitingPARP comprising causing a compound of any one of the above embodimentsand variations to be present in a subject in order to inhibit PARP invivo.

In a further of its aspects, there is provided a method of inhibitingPARP comprising administering a first compound to a subject that isconverted in vivo to a second compound wherein the second compoundinhibits PARP in vivo, the second compound being a compound according toany one of the above embodiments and variations.

In another of its aspects, there is provided a method of treating adisease state for which PARP possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising causing a compound of any one of the above embodiments andvariations to be present in a subject in a therapeutically effectiveamount for the disease state.

In yet another of its aspects, there is provided a method of treating adisease state for which PARP possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising administering a compound of any one of the above embodimentsand variations to a subject, wherein the compound is present in thesubject in a therapeutically effective amount for the disease state.

In a further of its aspects, there is provided a method of treating adisease state for which PARP possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibits PARPin vivo, the second compound being a compound according to any one ofthe above embodiments and variations.

In one variation of each of the above methods the disease state isselected from the group consisting of cancers (including cancers whereDNA damaging (e.g., alkylating) agents, cytotoxic drugs, radiationtherapy and/or topoisomerase inhibitors are a standard of care (e.g., incombination with chemo- and/or radiosensitizers for cancer treatment);cancers which are deficient in Homologous Recombination (HR) dependentDNA DSB repair; BRCA-I and BRCA-2 deficient tumors; bladder cancer;blood-borne cancers (e.g., acute lymphoblastic leukemia (“ALL”), acutelymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia,acute myeloblasts leukemia (“AML”), acute promyelocytic leukemia(“APL”), acute monoblastic leukemia, acute erythroleukemic leukemia,acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acutenonlymphocyctic leukemia, acute undifferentiated leukemia, chronicmyelocytic leukemia (“CML”), chronic lymphocytic leukemia (“CLL”), hairycell leukemia and multiple myeloma); bone cancer; breast cancer;carcinomas (e.g., squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, bileduct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, smallcell lung carcinoma, bladder carcinoma and epithelial carcinoma); CNSand brain cancers (e.g., glioma (e.g., pilocytic astrocytoma,astrocytoma, anaplastic astrocytoma, or glioblastoma multiforms),pilocytic astrocytoma, astrocytoma, anaplastic astrocytoma, glioblastomamultiforme, medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,vestibular schwannoma, adenoma, metastatic brain cancer, meningioma,spinal tumor and medulloblastoma); cervical cancer; colon cancer;colorectal cancer; esophageal cancer; hepatomas; head and neck cancer;kidney cancer; acute and chronic leukemias (e.g., lymphoblastic,myelogenous, lymphocytic and myelocytic leukemias); liver cancer; lungcancer; lymphomas (e.g., such as Hodgkin's disease, non-Hodgkin'sLymphoma, Multiple myeloma, Waldenstrom's macroglobulinemia, Heavy chaindisease and Polycythemia vera); melanomas; nasal cancer; neuroblastomas;oral cancer; ovarian cancer; pancreatic cancer; prostate cancer;retinoblastomas; skin cancer; solid tumors (e.g., such as fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma and rhabdomyosarcoma); stomach cancer; testicular cancer;throat cancer; uterine cancer and Wilms' tumor); cardiovascular diseases(including chronic heart failure; atherosclerosis; congestive heartfailure; circulatory shock; cardiomyopathy; cardiac transplant;myocardialinfarction and cardiac arrhythmia (e.g., atrial fibrillation,supraventricular tachycardia, atrial flutter and paroxysmal atrialtachycardia)); vascular diseases other than cardiovascular diseases(including peripheral arterial occlusion; thromboangitis obliterans;Reynaud's disease and phenomenon; acrocyanosis; erythromelalgia; venousthrombosis; varicose veins; arteriovenous fistula; lymphedema andlipedema); metabolic diseases (including diabetes (e.g., diabetesmellitus (e.g., Type I diabetes (Insulin Dependent Diabetes Mellitus),Type II diabetes (Non-Insulin Dependent Diabetes Mellitus), gestationaldiabetes, autoimmune diabetes, insulinopathies, diabetes due topancreatic disease, diabetes associated with other endocrine diseases(such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma,primary aldosteronism or somatostatinoma), Type A insulin resistancesyndrome, Type B insulin resistance syndrome, lipatrophic diabetes, anddiabetes induced by (β-cell toxins); and diabetic complications (e.g.,diabetic cataract, glaucoma, retinopathy, nephropathy (e.g.,microaluminuria and diabetic nephropathy), mononeuropathy, autonomicneuropathy, polyneuropathy, gangrene of the feet, atheroscleroticcoronary arterial disease, peripheral arterial disease, non-ketotichyperglycemic-hyperosmolar coma, mononeuropathies, autonomic neuropathy,foot ulcers, joint problems, skin or mucous membrane complications(e.g., infection, shin spot, candidal infection or necrobiosis lipoidicadiabeticorumobesity), hyperlipidemia, hypertension, syndrome of insulinresistance, coronary artery disease, foot ulcers, joint problems, fungalinfections, bacterial infections, cardiomyopathy, immune-complexvasculitis and systemic lupus erythematosus (SLE))); inflammatorydiseases (including conditions resulting from organ transplantrejection; chronic inflammatory diseases of the joints (e.g., arthritis,rheumatoid arthritis, osteoarthritis and bone diseases associated withincreased bone resorption); inflammatory bowel diseases (e.g., ileitis,ulcerative colitis, Barrett's syndrome and Crohn's disease);inflammatory lung diseases (e.g., asthma, adult respiratory distresssyndrome and chronic obstructive airway disease); inflammatory diseasesof the eye (e.g., corneal dystrophy, trachoma, onchocerciasis, uveitis,sympatheticophthalmitis and endophthalmitis); chronic inflammatorydiseases of the gum (e.g., gingivitis and periodontitis); tuberculosis;leprosy; inflammatory diseases of the kidney (e.g., uremiccomplications, glomerulonephritis and nephrosis); inflammatory diseasesof the skin (e.g., sclerodermatitis, psoriasis and eczema); inflammatorydiseases of the central nervous system (e.g., chronic demyelinatingdiseases of the nervous system, multiple sclerosis, AIDS-relatedneurodegeneration, Alzheimer's disease, infectious meningitis,encephalomyelitis, Parkinson's disease, Huntington's disease,amyotrophic lateral sclerosis and viral or autoimmune encephalitis);inflammatory diseases of the heart (e.g., cardiomyopathy, ischemic heartdisease, hypercholesterolemia and atherosclerosis); diseases that canhave significant inflammatory components (e.g., preeclampsia, chronicliver failure, brain and spinal cord trauma and multiple organdysfunction syndrome (MODS) (multiple organ failure (MOF))); systemicinflammation of the body, exemplified by gram-positive or gram negativeshock, hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, (e.g., shockassociated with pro-inflammatory cytokines; and shock induced, forexample, by a chemotherapeutic agent that is administered as a treatmentfor cancer); reperfusion injuries, including those resulting fromnaturally occurring episodes and during a surgical procedure (e.g.,intestinal reperfusion injury; myocardial reperfusion injury;reperfusion injury resulting from cardiopulmonary bypass surgery, aorticaneurysm repair surgery, carotid endarterectomy surgery, or hemorrhagicshock; and reoxygenation injury resulting from transplantation of organssuch as heart, lung, liver, kidney, pancreas, intestine or cornea);ischemic conditions, including those resulting from organtransplantation (e.g., stable angina, unstable angina, myocardialischemia, hepatic ischemia, mesenteric artery ischemia, intestinalischemia, critical limb ischemia, chronic critical limb ischemia,cerebral ischemia, acute cardiac ischemia, ischemic kidney disease,ischemic liver disease, ischemic retinal disorder, septic shock; and anischemic disease of the central nervous system (e.g., stroke or cerebralischemia)); neurodegenerative diseases (e.g.,polyglutamine-expansion-related neurodegeneration, Huntington's disease,Kennedy's disease, spinocerebellar ataxia, dentatorubral-pallidoluysianatrophy (DRPLA), protein-aggregation-related neurodegeneration,Machado-Joseph's disease, Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis, spongiform encephalopathy, aprion-related disease and multiple sclerosis (MS)); tissue injuries; CNSdiseases; heart attack; hematolymphoid system disorders; endocrine andneuroendocrine system disorders; urinary tract disorders; respiratorysystem disorders; female reproductive system disorders; malereproductive system disorders; retroviral infections; retinal damage;skin senescence; UV-induced skin damage; chronic or acute renal diseaseor failure; age-related cellular dysfunction; and fatty acid synthesisrelated diseases (e.g., obesity, diabetes and cardiovascular disease).

In another variation of each of the above methods, the PARP is a PARP-1,PARP-2, PARP-3, vaultPARP or TiPARP. It is noted that the compounds ofthe present invention may also possess inhibitory activity for otherPARP family members and thus may be used to address disease statesassociated with these other family members. Further, the compounds ofthe present invention may also possess inhibitory activity fortankyrases (e.g., tankyrase-1 and tankyrase-2) and thus may be used toaddress disease states associated with these target proteins.

Salts, Hydrates, and Prodrugs of PARP Inhibitors

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, hydratesand prodrugs that are converted in vivo into the compounds of thepresent invention. For example, it is within the scope of the presentinvention to convert the compounds of the present invention into and usethem in the form of their pharmaceutically acceptable salts derived fromvarious organic and inorganic acids and bases in accordance withprocedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids and their corresponding salts such as sulfate, nitrate,phosphate, etc.; and alkyl and monoarylsulfonates such asethanesulfonate, toluenesulfonate and benzenesulfonate; and otherorganic acids and their corresponding salts such as acetate, tartrate,maleate, succinate, citrate, benzoate, salicylate and ascorbate. Furtheracid addition salts of the present invention include, but are notlimited to: adipate, alginate, arginate, aspartate, bisulfate,bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate,chloride, chlorobenzoate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,galacterate (from mucic acid), galacturonate, glucoheptonate, gluconate,glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,lactobionate, malate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate and phthalate. It should be recognized that the free baseforms will typically differ from their respective salt forms somewhat inphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free base forms for thepurposes of the present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g., potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine(tromethamine). It should be recognized that the free acid forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid forms for the purposes ofthe present invention.

N-oxides of compounds according to the present invention can be preparedby methods known to those of ordinary skill in the art. For example,N-oxides can be prepared by treating an unoxidized form of the compoundwith an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid,perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or thelike) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds can be prepared from theN-oxide of an appropriate starting material.

Prodrug derivatives of compounds according to the present invention canbe prepared by modifying substituents of compounds of the presentinvention that are then converted in vivo to a different substituent. Itis noted that in many instances, the prodrugs themselves also fallwithin the scope of the range of compounds according to the presentinvention. For example, prodrugs can be prepared by reacting a compoundwith a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like) or an acylating agent. Furtherexamples of methods of making prodrugs are described in Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.

Protected derivatives of compounds of the present invention can also bemade. Examples of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, Protecting Groupsin Organic Synthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may also be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

A “pharmaceutically acceptable salt”, as used herein, is intended toencompass any compound according to the present invention that isutilized in the form of a salt thereof, especially where the saltconfers on the compound improved pharmacokinetic properties as comparedto the free form of compound or a different salt form of the compound.The pharmaceutically acceptable salt form may also initially conferdesirable pharmacokinetic properties on the compound that it did notpreviously possess, and may even positively affect the pharmacodynamicsof the compound with respect to its therapeutic activity in the body. Anexample of a pharmacokinetic property that may be favorably affected isthe manner in which the compound is transported across cell membranes,which in turn may directly and positively affect the absorption,distribution, biotransformation and excretion of the compound. While theroute of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological factors cancritically affect bioavailability, the solubility of the compound isusually dependent upon the character of the particular salt formthereof, which it utilized. One of skill in the art will appreciate thatan aqueous solution of the compound will provide the most rapidabsorption of the compound into the body of a subject being treated,while lipid solutions and suspensions, as well as solid dosage forms,will result in less rapid absorption of the compound.

Compositions Comprising PARP Inhibitors

A wide variety of compositions and administration methods may be used inconjunction with the compounds of the present invention. Suchcompositions may include, in addition to the compounds of the presentinvention, conventional pharmaceutical excipients, and otherconventional, pharmaceutically inactive agents. Additionally, thecompositions may include active agents in addition to the compounds ofthe present invention. These additional active agents may includeadditional compounds according to the invention, and/or one or moreother pharmaceutically active agents.

The compositions may be in gaseous, liquid, semi-liquid or solid form,formulated in a manner suitable for the route of administration to beused. For oral administration, capsules and tablets are typically used.For parenteral administration, reconstitution of a lyophilized powder,prepared as described herein, is typically used.

Compositions comprising compounds of the present invention may beadministered or coadministered orally, parenterally, intraperitoneally,intravenously, intraarterially, transdermally, sublingually,intramuscularly, rectally, transbuccally, intranasally, liposomally, viainhalation, vaginally, intraoccularly, via local delivery (for exampleby catheter or stent), subcutaneously, intraadiposally,intraarticularly, or intrathecally. The compounds and/or compositionsaccording to the invention may also be administered or coadministered inslow release dosage forms.

The PARP inhibitors and compositions comprising them may be administeredor coadministered in any conventional dosage form. Co-administration inthe context of this invention is intended to mean the administration ofmore than one therapeutic agent, one of which includes a PARP inhibitor,in the course of a coordinated treatment to achieve an improved clinicaloutcome. Such co-administration may also be coextensive, that is,occurring during overlapping periods of time.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application may optionally include one or more of thefollowing components: a sterile diluent, such as water for injection,saline solution, fixed oil, polyethylene glycol, glycerine, propyleneglycol or other synthetic solvent; antimicrobial agents, such as benzylalcohol and methyl parabens; antioxidants, such as ascorbic acid andsodium bisulfite; chelating agents, such as ethylenediaminetetraaceticacid (EDTA); buffers, such as acetates, citrates and phosphates; agentsfor the adjustment of tonicity such as sodium chloride or dextrose, andagents for adjusting the acidity or alkalinity of the composition, suchas alkaline or acidifying agents or buffers like carbonates,bicarbonates, phosphates, hydrochloric acid, and organic acids likeacetic and citric acid. Parenteral preparations may optionally beenclosed in ampules, disposable syringes or single or multiple dosevials made of glass, plastic or other suitable material.

When compounds according to the present invention exhibit insufficientsolubility, methods for solubilizing the compounds may be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, using cosolvents, such as dimethylsulfoxide (DMSO),using surfactants, such as TWEEN, or dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as prodrugs of thecompounds may also be used in formulating effective pharmaceuticalcompositions.

Upon mixing or adding compounds according to the present invention to acomposition, a solution, suspension, emulsion or the like may be formed.The form of the resulting composition will depend upon a number offactors, including the intended mode of administration, and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration needed to ameliorate the disease being treatedmay be empirically determined.

Compositions according to the present invention are optionally providedfor administration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, dry powders for inhalers, granules,sterile parenteral solutions or suspensions, and oral solutions orsuspensions, and oil-water emulsions containing suitable quantities ofthe compounds, particularly the pharmaceutically acceptable salts,preferably the sodium salts, thereof. The pharmaceuticallytherapeutically active compounds and derivatives thereof are typicallyformulated and administered in unit-dosage forms or multiple-dosageforms. Unit-dose forms, as used herein, refers to physically discreteunits suitable for human and animal subjects and packaged individuallyas is known in the art. Each unit-dose contains a predetermined quantityof the therapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes individually packaged tablet or capsule. Unit-doseforms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pint or gallons. Hence, multipledose form is a multiple of unit-doses that are not segregated inpackaging.

In addition to one or more compounds according to the present invention,the composition may comprise: a diluent such as lactose, sucrose,dicalcium phosphate, or carboxymethylcellulose; a lubricant, such asmagnesium stearate, calcium stearate and talc; and a binder such asstarch, natural gums, such as gum acaciagelatin, glucose, molasses,polyinylpyrrolidine, celluloses and derivatives thereof, povidone,crospovidones and other such binders known to those of skill in the art.Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of auxiliary substances suchas wetting agents, emulsifying agents, or solubilizing agents, pHbuffering agents and the like, for example, acetate, sodium citrate,cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodiumacetate, triethanolamine oleate, and other such agents. Actual methodsof preparing such dosage forms are known in the art, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975. The composition or formulation to be administered will,in any event, contain a sufficient quantity of an inhibitor of thepresent invention to reduce PARP activity in vivo, thereby treating thedisease state of the subject.

Dosage forms or compositions may optionally comprise one or morecompounds according to the present invention in the range of 0.005% to100% (weight/weight) with the balance comprising additional substancessuch as those described herein. For oral administration, apharmaceutically acceptable composition may optionally comprise any oneor more commonly employed excipients, such as, for examplepharmaceutical grades of mannitol, lactose, starch, magnesium stearate,talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose,magnesium carbonate, sodium saccharin, talcum. Such compositions includesolutions, suspensions, tablets, capsules, powders, dry powders forinhalers and sustained release formulations, such as, but not limitedto, implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers, such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid andothers. Methods for preparing these formulations are known to thoseskilled in the art. The compositions may optionally contain 0.01%-100%(weight/weight) of one or more PARP inhibitors, optionally 0.1-95%, andoptionally 1-95%.

Salts, preferably sodium salts, of the inhibitors may be prepared withcarriers that protect the compound against rapid elimination from thebody, such as time release formulations or coatings. The formulationsmay further include other active compounds to obtain desiredcombinations of properties.

Formulations for Oral Administration

Oral pharmaceutical dosage forms may be as a solid, gel or liquid.Examples of solid dosage forms include, but are not limited to tablets,capsules, granules, and bulk powders. More specific examples of oraltablets include compressed, chewable lozenges and tablets that may beenteric-coated, sugar-coated or film-coated. Examples of capsulesinclude hard or soft gelatin capsules. Granules and powders may beprovided in non-effervescent or effervescent forms. Each may be combinedwith other ingredients known to those skilled in the art.

In certain embodiments, compounds according to the present invention areprovided as solid dosage forms, preferably capsules or tablets. Thetablets, pills, capsules, troches and the like may optionally containone or more of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders that may be used include, but are not limited to,microcrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, sucrose, and starch paste.

Examples of lubricants that may be used include, but are not limited to,talc, starch, magnesium or calcium stearate, lycopodium and stearicacid.

Examples of diluents that may be used include, but are not limited to,lactose, sucrose, starch, kaolin, salt, mannitol, and dicalciumphosphate.

Examples of glidants that may be used include, but are not limited to,colloidal silicon dioxide.

Examples of disintegrating agents that may be used include, but are notlimited to, crosscarmellose sodium, sodium starch glycolate, alginicacid, corn starch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose.

Examples of coloring agents that may be used include, but are notlimited to, any of the approved certified water-soluble FD and C dyes,mixtures thereof; and water insoluble FD and C dyes suspended on aluminahydrate.

Examples of sweetening agents that may be used include, but are notlimited to, sucrose, lactose, mannitol and artificial sweetening agentssuch as sodium cyclamate and saccharin, and any number of spray-driedflavors.

Examples of flavoring agents that may be used include, but are notlimited to, natural flavors extracted from plants such as fruits andsynthetic blends of compounds that produce a pleasant sensation, suchas, but not limited to peppermint and methyl salicylate.

Examples of wetting agents that may be used include, but are not limitedto, propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether.

Examples of anti-emetic coatings that may be used include, but are notlimited to, fatty acids, fats, waxes, shellac, ammoniated shellac andcellulose acetate phthalates.

Examples of film coatings that may be used include, but are not limitedto, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the salt of the compound mayoptionally be provided in a composition that protects it from the acidicenvironment of the stomach. For example, the composition can beformulated in an enteric coating that maintains its integrity in thestomach and releases the active compound in the intestine. Thecomposition may also be formulated in combination with an antacid orother such ingredient.

When the dosage unit form is a capsule, it may optionally additionallycomprise a liquid carrier such as a fatty oil. In addition, dosage unitforms may optionally additionally comprise various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents.

Compounds according to the present invention may also be administered asa component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may optionally comprise, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The compounds of the present invention may also be mixed with otheractive materials that do not impair the desired action, or withmaterials that supplement the desired action, such as antacids, H2blockers, and diuretics. For example, if a compound is used for treatingasthma or hypertension, it may be used with other bronchodilators andantihypertensive agents, respectively.

Examples of pharmaceutically acceptable carriers that may be included intablets comprising compounds of the present invention include, but arenot limited to binders, lubricants, diluents, disintegrating agents,coloring agents, flavoring agents, and wetting agents. Enteric-coatedtablets, because of the enteric-coating, resist the action of stomachacid and dissolve or disintegrate in the neutral or alkaline intestines.Sugar-coated tablets may be compressed tablets to which different layersof pharmaceutically acceptable substances are applied. Film-coatedtablets may be compressed tablets that have been coated with polymers orother suitable coating. Multiple compressed tablets may be compressedtablets made by more than one compression cycle utilizing thepharmaceutically acceptable substances previously mentioned. Coloringagents may also be used in tablets. Flavoring and sweetening agents maybe used in tablets, and are especially useful in the formation ofchewable tablets and lozenges.

Examples of liquid oral dosage forms that may be used include, but arenot limited to, aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules.

Examples of aqueous solutions that may be used include, but are notlimited to, elixirs and syrups. As used herein, elixirs refer to clear,sweetened, hydroalcoholic preparations. Examples of pharmaceuticallyacceptable carriers that may be used in elixirs include, but are notlimited to solvents. Particular examples of solvents that may be usedinclude glycerin, sorbitol, ethyl alcohol and syrup. As used herein,syrups refer to concentrated aqueous solutions of a sugar, for example,sucrose. Syrups may optionally further comprise a preservative.

Emulsions refer to two-phase systems in which one liquid is dispersed inthe form of small globules throughout another liquid. Emulsions mayoptionally be oil-in-water or water-in-oil emulsions. Examples ofpharmaceutically acceptable carriers that may be used in emulsionsinclude, but are not limited to non-aqueous liquids, emulsifying agentsand preservatives.

Examples of pharmaceutically acceptable substances that may be used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents.

Examples of pharmaceutically acceptable substances that may be used ineffervescent granules, to be reconstituted into a liquid oral dosageform, include organic acids and a source of carbon dioxide.

Coloring and flavoring agents may optionally be used in all of the abovedosage forms.

Particular examples of preservatives that may be used include glycerin,methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

Particular examples of non-aqueous liquids that may be used in emulsionsinclude mineral oil and cottonseed oil.

Particular examples of emulsifying agents that may be used includegelatin, acacia, tragacanth, bentonite, and surfactants such aspolyoxyethylene sorbitan monooleate.

Particular examples of suspending agents that may be used include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluentsinclude lactose and sucrose. Sweetening agents include sucrose, syrups,glycerin and artificial sweetening agents such as sodium cyclamate andsaccharin.

Particular examples of wetting agents that may be used include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurateand polyoxyethylene lauryl ether.

Particular examples of organic acids that may be used include citric andtartaric acid.

Sources of carbon dioxide that may be used in effervescent compositionsinclude sodium bicarbonate and sodium carbonate. Coloring agents includeany of the approved certified water soluble FD and C dyes, and mixturesthereof.

Particular examples of flavoring agents that may be used include naturalflavors extracted from plants such fruits, and synthetic blends ofcompounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603.

Injectables, Solutions, and Emulsions

The present invention is also directed to compositions designed toadminister the compounds of the present invention by parenteraladministration, generally characterized by subcutaneous, intramuscularor intravenous injection. Injectables may be prepared in anyconventional form, for example as liquid solutions or suspensions, solidforms suitable for solution or suspension in liquid prior to injection,or as emulsions.

Examples of excipients that may be used in conjunction with injectablesaccording to the present invention include, but are not limited towater, saline, dextrose, glycerol or ethanol. The injectablecompositions may also optionally comprise minor amounts of non-toxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents, stabilizers, solubility enhancers, and other such agents, suchas for example, sodium acetate, sorbitan monolaurate, triethanolamineoleate and cyclodextrins. Implantation of a slow-release orsustained-release system, such that a constant level of dosage ismaintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplatedherein. The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject.

Parenteral administration of the formulations includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as the lyophilized powders describedherein, ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior to useand sterile emulsions. The solutions may be either aqueous ornonaqueous.

When administered intravenously, examples of suitable carriers include,but are not limited to physiological saline or phosphate buffered saline(PBS), and solutions containing thickening and solubilizing agents, suchas glucose, polyethylene glycol, and polypropylene glycol and mixturesthereof.

Examples of pharmaceutically acceptable carriers that may optionally beused in parenteral preparations include, but are not limited to aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersingagents, emulsifying agents, sequestering or chelating agents and otherpharmaceutically acceptable substances.

Examples of aqueous vehicles that may optionally be used include SodiumChloride Injection, Ringers Injection, Isotonic Dextrose Injection,Sterile Water Injection, Dextrose and Lactated Ringers Injection.

Examples of nonaqueous parenteral vehicles that may optionally be usedinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil.

Antimicrobial agents in bacteriostatic or fungistatic concentrations maybe added to parenteral preparations, particularly when the preparationsare packaged in multiple-dose containers and thus designed to be storedand multiple aliquots to be removed. Examples of antimicrobial agentsthat may be used include phenols or cresols, mercurials, benzyl alcohol,chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride and benzethonium chloride.

Examples of isotonic agents that may be used include sodium chloride anddextrose. Examples of buffers that may be used include phosphate andcitrate. Examples of antioxidants that may be used include sodiumbisulfate. Examples of local anesthetics that may be used includeprocaine hydrochloride. Examples of suspending and dispersing agentsthat may be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of emulsifying agentsthat may be used include Polysorbate 80 (TWEEN 80). A sequestering orchelating agent of metal ions includes EDTA.

Pharmaceutical carriers may also optionally include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles andsodium hydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment.

The concentration of an inhibitor in the parenteral formulation may beadjusted so that an injection administers a pharmaceutically effectiveamount sufficient to produce the desired pharmacological effect. Theexact concentration of an inhibitor and/or dosage to be used willultimately depend on the age, weight and condition of the patient oranimal as is known in the art.

Unit-dose parenteral preparations may be packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration should be sterile, as is known and practiced in the art.

Injectables may be designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the PARP inhibitor to the treatedtissue(s). The inhibitor may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment willbe a function of the location of where the composition is parenterallyadministered, the carrier and other variables that may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test data. It is to be noted that concentrations anddosage values may also vary with the age of the individual treated. Itis to be further understood that for any particular subject, specificdosage regimens may need to be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the formulations.Hence, the concentration ranges set forth herein are intended to beexemplary and are not intended to limit the scope or practice of theclaimed formulations.

The PARP inhibitor may optionally be suspended in micronized or othersuitable form or may be derivatized to produce a more soluble activeproduct or to produce a prodrug. The form of the resulting mixturedepends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease state and may be empiricallydetermined.

Lyophilized Powders

The compounds of the present invention may also be prepared aslyophilized powders, which can be reconstituted for administration assolutions, emulsions and other mixtures. The lyophilized powders mayalso be formulated as solids or gels.

Sterile, lyophilized powder may be prepared by dissolving the compoundin a sodium phosphate buffer solution containing dextrose or othersuitable excipient. Subsequent sterile filtration of the solutionfollowed by lyophilization under standard conditions known to those ofskill in the art provides the desired formulation. Briefly, thelyophilized powder may optionally be prepared by dissolving dextrose,sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose orother suitable agent, about 1-20%, preferably about 5 to 15%, in asuitable buffer, such as citrate, sodium or potassium phosphate or othersuch buffer known to those of skill in the art at, typically, aboutneutral pH. Then, a PARP inhibitor is added to the resulting mixture,preferably above room temperature, more preferably at about 30-35° C.,and stirred until it dissolves. The resulting mixture is diluted byadding more buffer to a desired concentration. The resulting mixture issterile filtered or treated to remove particulates and to insuresterility, and apportioned into vials for lyophilization. Each vial maycontain a single dosage or multiple dosages of the inhibitor.

Topical Administration

The compounds of the present invention may also be administered astopical mixtures. Topical mixtures may be used for local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The PARP inhibitors may be formulated as aerosols for topicalapplication, such as by inhalation (see, U.S. Pat. Nos. 4,044,126,4,414,209, and 4,364,923, which describe aerosols for delivery of asteroid useful for treatment of inflammatory diseases, particularlyasthma). These formulations for administration to the respiratory tractcan be in the form of an aerosol or solution for a nebulizer, or as amicrofine powder for insufflation, alone or in combination with an inertcarrier such as lactose. In such a case, the particles of theformulation will typically have diameters of less than 50 microns,preferably less than 10 microns.

The inhibitors may also be formulated for local or topical application,such as for topical application to the skin and mucous membranes, suchas in the eye, in the form of gels, creams, and lotions and forapplication to the eye or for intracisternal or intraspinal application.Topical administration is contemplated for transdermal delivery and alsofor administration to the eyes or mucosa, or for inhalation therapies.Nasal solutions of the PARP inhibitor alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

Formulations for Other Routes of Administration

Depending upon the disease state being treated, other routes ofadministration, such as topical application, transdermal patches, andrectal administration, may also be used. For example, pharmaceuticaldosage forms for rectal administration are rectal suppositories,capsules and tablets for systemic effect. Rectal suppositories are usedherein mean solid bodies for insertion into the rectum that melt orsoften at body temperature releasing one or more pharmacologically ortherapeutically active ingredients. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethyleneglycol) and appropriate mixtures of mono-, di- and triglycerides offatty acids. Combinations of the various bases may be used. Agents toraise the melting point of suppositories include spermaceti and wax.Rectal suppositories may be prepared either by the compressed method orby molding. The typical weight of a rectal suppository is about 2 to 3gm. Tablets and capsules for rectal administration may be manufacturedusing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

Examples of Formulations

The following are particular examples of oral, intravenous and tabletformulations that may optionally be used with compounds of the presentinvention. It is noted that these formulations may be varied dependingon the particular compound being used and the indication for which theformulation is going to be used.

ORAL FORMULATION Compound of the Present Invention 10-100 mg Citric AcidMonohydrate 105 mg Sodium Hydroxide 18 mg Flavoring q.s. to 100 mL WaterINTRAVENOUS FORMULATION Compound of the Present Invention 0.1-10 mgDextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL TABLETFORMULATION Compound of the Present Invention  1% MicrocrystallineCellulose 73% Stearic Acid 25% Colloidal Silica   1%.Kits Comprising PARP Inhibitors

The invention is also directed to kits and other articles of manufacturefor treating diseases associated with PARP. It is noted that diseasesare intended to cover all conditions for which the PARP possess activitythat contributes to the pathology and/or symptomology of the condition.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one inhibitor of the presentinvention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

It is noted that the packaging material used in kits and articles ofmanufacture according to the present invention may form a plurality ofdivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container that is employed will depend on the exact dosage forminvolved, for example a conventional cardboard box would not generallybe used to hold a liquid suspension. It is feasible that more than onecontainer can be used together in a single package to market a singledosage form. For example, tablets may be contained in a bottle that isin turn contained within a box. Typically the kit includes directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral, topical, transdermaland parenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

One particular example of a kit according to the present invention is aso-called blister pack. Blister packs are well known in the packagingindustry and are being widely used for the packaging of pharmaceuticalunit dosage forms (tablets, capsules, and the like). Blister packsgenerally consist of a sheet of relatively stiff material covered with afoil of a preferably transparent plastic material. During the packagingprocess recesses are formed in the plastic foil. The recesses have thesize and shape of individual tablets or capsules to be packed or mayhave the size and shape to accommodate multiple tablets and/or capsulesto be packed. Next, the tablets or capsules are placed in the recessesaccordingly and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are individually sealed or collectively sealed, as desired, inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

Another specific embodiment of a kit is a dispenser designed to dispensethe daily doses one at a time in the order of their intended use.Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter that indicates the number of dailydoses that has been dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

Dosage, Host and Safety

The compounds of the present invention are stable and can be usedsafely. In particular, the compounds of the present invention are usefulas PARP inhibitors for a variety of subjects (e.g., humans, non-humanmammals and non-mammals). The optimal dose may vary depending upon suchconditions as, for example, the type of subject, the body weight of thesubject, the route of administration, and specific properties of theparticular compound being used. In general, the daily dose for oraladministration to an adult (body weight of about 60 kg) is about 1 to1000 mg, about 3 to 300 mg, or about 10 to 200 mg. It will beappreciated that the daily dose can be given in a single administrationor in multiple (e.g., 2 or 3) portions a day.

Combination Therapies

A wide variety therapeutic agents may have a therapeutic additive orsynergistic effect with PARP inhibitors according to the presentinvention. Combination therapies that comprise one or more compounds ofthe present invention with one or more other therapeutic agents can beused, for example, to: 1) enhance the therapeutic effect(s) of the oneor more compounds of the present invention and/or the one or more othertherapeutic agents; 2) reduce the side effects exhibited by the one ormore compounds of the present invention and/or the one or more othertherapeutic agents; and/or 3) reduce the effective dose of the one ormore compounds of the present invention and/or the one or more othertherapeutic agents.

In one embodiment, a method is provided for treating a cellproliferative disease state comprising treating cells with a compoundaccording to the present invention in combination with ananti-proliferative agent, wherein the cells are treated with thecompound according to the present invention before, at the same time,and/or after the cells are treated with the anti-proliferative agent,referred to herein as combination therapy. It is noted that treatment ofone agent before another is referred to herein as sequential therapy,even if the agents are also administered together. It is noted thatcombination therapy is intended to cover when agents are administeredbefore or after each other (sequential therapy) as well as when theagents are administered at the same time.

Examples of therapeutic agents that may be used in combination with PARPinhibitors include, but are not limited to, anticancer agents,alkylating agents, antibiotic agents, antimetabolic agents, hormonalagents, plant-derived agents, and biologic agents.

Alkylating agents are polyfunctional compounds that have the ability tosubstitute alkyl groups for hydrogen ions. Examples of alkylating agentsinclude, but are not limited to, bischloroethylamines (nitrogenmustards, e.g. chlorambucil, cyclophosphamide, ifosfamide,mechlorethamine, melphalan, uracil mustard), aziridines (e.g. thiotepa),alkyl alkone sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine,lomustine, streptozocin), nonclassic alkylating agents (altretamine,dacarbazine, and procarbazine), platinum compounds (carboplastin andcisplatin). These compounds react with phosphate, amino, hydroxyl,sulfihydryl, carboxyl, and imidazole groups. Under physiologicalconditions, these drugs ionize and produce positively charged ion thatattach to susceptible nucleic acids and proteins, leading to cell cyclearrest and/or cell death. Combination therapy including a PARP inhibitorand an alkylating agent may have therapeutic synergistic effects oncancer and reduce sides affects associated with these chemotherapeuticagents.

Antibiotic agents are a group of drugs that are produced in a mannersimilar to antibiotics as a modification of natural products. Examplesof antibiotic agents include, but are not limited to, anthracyclines(e.g. doxorubicin, daunorubicin, epirubicin, idarubicin andanthracenedione), mitomycin C, bleomycin, dactinomycin, plicatomycin.These antibiotic agents interfere with cell growth by targetingdifferent cellular components. For example, anthracyclines are generallybelieved to interfere with the action of DNA topoisomerase II in theregions of transcriptionally active DNA, which leads to DNA strandscissions. Bleomycin is generally believed to chelate iron and forms anactivated complex, which then binds to bases of DNA, causing strandscissions and cell death. Combination therapy including a PARP inhibitorand an antibiotic agent may have therapeutic synergistic effects oncancer and reduce sides affects associated with these chemotherapeuticagents.

Antimetabolic agents are a group of drugs that interfere with metabolicprocesses vital to the physiology and proliferation of cancer cells.Actively proliferating cancer cells require continuous synthesis oflarge quantities of nucleic acids, proteins, lipids, and other vitalcellular constituents. Many of the antimetabolites inhibit the synthesisof purine or pyrimidine nucleosides or inhibit the enzymes of DNAreplication. Some antimetabolites also interfere with the synthesis ofribonucleosides and RNA and/or amino acid metabolism and proteinsynthesis as well. By interfering with the synthesis of vital cellularconstituents, antimetabolites can delay or arrest the growth of cancercells. Examples of antimetabolic agents include, but are not limited to,fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate, leucovorin,hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine,pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase,and gemcitabine. Combination therapy including a PARP inhibitor and aantimetabolic agent may have therapeutic synergistic effects on cancerand reduce sides affects associated with these chemotherapeutic agents.

Hormonal agents are a group of drug that regulate the growth anddevelopment of their target organs. Most of the hormonal agents are sexsteroids and their derivatives and analogs thereof, such as estrogens,androgens, and progestins. These hormonal agents may serve asantagonists of receptors for the sex steroids to down regulate receptorexpression and transcription of vital genes. Examples of such hormonalagents are synthetic estrogens (e.g. diethylstibestrol), antiestrogens(e.g. tamoxifen, toremifene, fluoxymesterol and raloxifene),antiandrogens (bicalutamide, nilutamide, flutamide), aromataseinhibitors (e.g., aminoglutethimide, anastrozole and tetrazole),ketoconazole, goserelin acetate, leuprolide, megestrol acetate andmifepristone. Combination therapy including a PARP inhibitor and ahormonal agent may have therapeutic synergistic effects on cancer andreduce sides affects associated with these chemotherapeutic agents.

Plant-derived agents are a group of drugs that are derived from plantsor modified based on the molecular structure of the agents. Examples ofplant-derived agents include, but are not limited to, vinca alkaloids(e.g., vincristine, vinblastine, vindesine, vinzolidine andvinorelbine), podophyllotoxins (e.g., etoposide (VP-16) and teniposide(VM-26)), taxanes (e.g., paclitaxel and docetaxel). These plant-derivedagents generally act as antimitotic agents that bind to tubulin andinhibit mitosis. Podophyllotoxins such as etoposide are believed tointerfere with DNA synthesis by interacting with topoisomerase II,leading to DNA strand scission. Combination therapy including a PARPinhibitor and a plant-derived agent may have therapeutic synergisticeffects on cancer and reduce sides affects associated with thesechemotherapeutic agents.

Biologic agents are a group of biomolecules that elicit cancer/tumorregression when used alone or in combination with chemotherapy and/orradiotherapy. Examples of biologic agents include, but are not limitedto, immuno-modulating proteins such as cytokines, monoclonal antibodiesagainst tumor antigens, tumor suppressor genes, and cancer vaccines.Combination therapy including a PARP inhibitor and a biologic agent mayhave therapeutic synergistic effects on cancer, enhance the patient'simmune responses to tumorigenic signals, and reduce potential sidesaffects associated with this chemotherapeutic agent.

Cytokines possess profound immunomodulatory activity. Some cytokinessuch as interleukin-2 (IL-2, aldesleukin) and interferon havedemonstrated antitumor activity and have been approved for the treatmentof patients with metastatic renal cell carcinoma and metastaticmalignant melanoma. IL-2 is a T-cell growth factor that is central toT-cell-mediated immune responses. The selective antitumor effects ofIL-2 on some patients are believed to be the result of a cell-mediatedimmune response that discriminate between self and nonself. Examples ofinterleukins that may be used in conjunction with PARP inhibitorinclude, but are not limited to, interleukin 2 (IL-2), and interleukin 4(IL-4), interleukin 12 (IL-12).

Interferon include more than 23 related subtypes with overlappingactivities, all of the IFN subtypes within the scope of the presentinvention. IFN has demonstrated activity against many solid andhematologic malignancies, the later appearing to be particularlysensitive.

Other cytokines that may be used in conjunction with a PARP inhibitorinclude those cytokines that exert profound effects on hematopoiesis andimmune functions. Examples of such cytokines include, but are notlimited to erythropoietin, granulocyte-CSF (filgrastin), andgranulocyte, macrophage-CSF (sargramostim). These cytokines may be usedin conjunction with a PARP inhibitor to reduce chemotherapy-inducedmyelopoietic toxicity.

Other immuno-modulating agents other than cytokines may also be used inconjunction with a PARP inhibitor to inhibit abnormal cell growth.Examples of such immuno-modulating agents include, but are not limitedto bacillus Calmette-Guerin, levamisole, and octreotide, a long-actingoctapeptide that mimics the effects of the naturally occurring hormonesomatostatin.

Monoclonal antibodies against tumor antigens are antibodies elicitedagainst antigens expressed by tumors, preferably tumor-specificantigens. For example, monoclonal antibody HERCEPTIN® (Trastruzumab) israised against human epidermal growth factor receptor2 (HER2) that isoverexpressed in some breast tumors including metastatic breast cancer.Overexpression of HER2 protein is associated with more aggressivedisease and poorer prognosis in the clinic. HERCEPTIN® is used as asingle agent for the treatment of patients with metastatic breast cancerwhose tumors over express the HER2 protein. Combination therapyincluding PARP inhibitor and HERCEPTIN® may have therapeutic synergisticeffects on tumors, especially on metastatic cancers.

Another example of monoclonal antibodies against tumor antigens isRITUXAN® (Rituximab) that is raised against CD20 on lymphoma cells andselectively deplete normal and malignant CD20⁺ pre-B and mature B cells.RITUXAN® is used as single agent for the treatment of patients withrelapsed or refractory low-grade or follicular, CD20+, B cellnon-Hodgkin's lymphoma. Combination therapy including PARP inhibitor andRITUXAN® may have therapeutic synergistic effects not only on lymphoma,but also on other forms or types of malignant tumors.

Tumor suppressor genes are genes that function to inhibit the cellgrowth and division cycles, thus preventing the development ofneoplasia. Mutations in tumor suppressor genes cause the cell to ignoreone or more of the components of the network of inhibitory signals,overcoming the cell cycle check points and resulting in a higher rate ofcontrolled cell growth—cancer. Examples of the tumor suppressor genesinclude, but are not limited to, DPC-4, NF-1, NF-2, RB, p53, WT1, BRCA1,and BRCA2.

DPC-4 is involved in pancreatic cancer and participates in a cytoplasmicpathway that inhibits cell division. NF-1 codes for a protein thatinhibits Ras, a cytoplasmic inhibitory protein. NF-1 is involved inneurofibroma and pheochromocytomas of the nervous system and myeloidleukemia. NF-2 encodes a nuclear protein that is involved in meningioma,schwanoma, and ependymoma of the nervous system. RB codes for the pRBprotein, a nuclear protein that is a major inhibitor of cell cycle. RBis involved in retinoblastoma as well as bone, bladder, small cell lungand breast cancer. P53 codes for p53 protein that regulates celldivision and can induce apoptosis. Mutation and/or inaction of p53 isfound in a wide ranges of cancers. WT1 is involved in Wilms tumor of thekidneys. BRCA1 is involved in breast and ovarian cancer, and BRCA2 isinvolved in breast cancer. The tumor suppressor gene can be transferredinto the tumor cells where it exerts its tumor suppressing functions.Combination therapy including a PARP inhibitor and a tumor suppressormay have therapeutic synergistic effects on patients suffering fromvarious forms of cancers.

Cancer vaccines are a group of agents that induce the body's specificimmune response to tumors. Most of cancer vaccines under research anddevelopment and clinical trials are tumor-associated antigens (TAAs).TAA are structures (i.e. proteins, enzymes or carbohydrates) which arepresent on tumor cells and relatively absent or diminished on normalcells. By virtue of being fairly unique to the tumor cell, TAAs providetargets for the immune system to recognize and cause their destruction.Example of TAAs include, but are not limited to gangliosides (GM2),prostate specific antigen (PSA), alpha-fetoprotein (AFP),carcinoembryonic antigen (CEA) (produced by colon cancers and otheradenocarcinomas, e.g. breast, lung, gastric, and pancreas cancer s),melanoma associated antigens (MART-1, gp100, MAGE 1,3 tyrosinase),papillomavirus E6 and E7 fragments, whole cells or portions/lysates ofantologous tumor cells and allogeneic tumor cells.

An adjuvant may be used to augment the immune response to TAAs. Examplesof adjuvants include, but are not limited to, bacillus Calmette-Guerin(BCG), endotoxin lipopolysaccharides, keyhole limpet hemocyanin (GKLH),interleukin-2 (IL-2), granulocyte-macrophage colony-stimulating factor(GM-CSF) and cytoxan, a chemotherapeutic agent which is believe toreduce tumor-induced suppression when given in low doses.

Further examples of therapeutic agents that may be used in combinationwith PARP inhibitors include, but are not limited to, Pl3/Akt signalinginhibitors. Examples of Pl3/Akt inhibitors that may be used incombination with PARP inhibitors include, but are not limited to, humanepidermal growth factor receptor (HER2) inhibitors. Examples of HER2inhibitors include, but are not limited to, Herceptin® (Trastruzumab)and Tykerb® (Lapatinib). Tykerb®, a small molecule that can beadministered orally, inhibits the tyrosine kinase components of ErbB 1and ErbB2 receptors. Stimulation of ErbB 1 and ErbB2 is associated withcell proliferation and with multiple processes involved in tumorprogression, invasion, and metastasis. Overexpression of these receptorshas been reported in a variety of human tumors and is associated withpoor prognosis and reduced overall survival.

Still further examples of therapeutic agents that may be used incombination with PARP inhibitors include, but are not limited to,histone deacetylase (HDAC) inhibitors. Examples of HDAC inhibitors thatmay be used in combination with PARP inhibitors include, but are notlimited to, suberoylanilide hydroxamic acid (SAHA).

In addition, the PARP inhibitors of the present invention may be used incombination with aminoglyside antiobiotics, CHK inhibitors, cytotoxicdrugs and/or topoisomerase inhibitors.

EXAMPLES

Preparation of PARP Inhibitors

Various methods may be developed for synthesizing compounds according tothe present invention. Representative methods for synthesizing thesecompounds are provided in the Examples. It is noted, however, that thecompounds of the present invention may also be synthesized by othersynthetic routes that others may devise.

It will be readily recognized that certain compounds according to thepresent invention have atoms with linkages to other atoms that confer aparticular stereochemistry to the compound (e.g., chiral centers). It isrecognized that synthesis of compounds according to the presentinvention may result in the creation of mixtures of differentstereoisomers (i.e., enantiomers and diastereomers). Unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all of the different possible stereoisomers.

Various methods for separating mixtures of different stereoisomers areknown in the art. For example, a racemic mixture of a compound may bereacted with an optically active resolving agent to form a pair ofdiastereoisomeric compounds. The diastereomers may then be separated inorder to recover the optically pure enantiomers. Dissociable complexesmay also be used to resolve enantiomers (e.g., crystallinediastereoisomeric salts). Diastereomers typically have sufficientlydistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) and can be readily separated by takingadvantage of these dissimilarities. For example, diastereomers cantypically be separated by chromatography or by separation/resolutiontechniques based upon differences in solubility. A more detaileddescription of techniques that can be used to resolve stereoisomers ofcompounds from their racemic mixture can be found in Jean Jacques AndreCollet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, JohnWiley & Sons, Inc. (1981).

Compounds according to the present invention can also be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a compound can be prepared by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base.Inorganic and organic acids and bases suitable for the preparation ofthe pharmaceutically acceptable salts of compounds are set forth in thedefinitions section of this application. Alternatively, the salt formsof the compounds can be prepared using salts of the starting materialsor intermediates.

The free acid or free base forms of the compounds can be prepared fromthe corresponding base addition salt or acid addition salt form. Forexample, a compound in an acid addition salt form can be converted tothe corresponding free base by treating with a suitable base (e.g.,ammonium hydroxide solution, sodium hydroxide, and the like). A compoundin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc).

The N-oxides of compounds according to the present invention can beprepared by methods known to those of ordinary skill in the art. Forexample, N-oxides can be prepared by treating an unoxidized form of thecompound with an oxidizing agent (e.g., trifluoroperacetic acid,permaleic acid, perbenzoic acid, peracetic acid,meta-chloroperoxybenzoic acid, or the like) in a suitable inert organicsolvent (e.g., a halogenated hydrocarbon such as dichloromethane) atapproximately 0° C. Alternatively, the N-oxides of the compounds can beprepared from the N-oxide of an appropriate starting material.

Compounds in an unoxidized form can be prepared from N-oxides ofcompounds by treating with a reducing agent (e.g., sulfur, sulfurdioxide, triphenyl phosphine, lithium borohydride, sodium borohydride,phosphorus trichloride, tribromide, or the like) in an suitable inertorganic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or thelike) at 0 to 80° C.

Prodrug derivatives of the compounds can be prepared by methods known tothose of ordinary skill in the art (e.g., for further details seeSaulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound with a suitable carbamylating agent(e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, orthe like).

Protected derivatives of the compounds can be made by methods known tothose of ordinary skill in the art. A detailed description of thetechniques applicable to the creation of protecting groups and theirremoval can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds according to the present invention may be convenientlyprepared, or formed during the process of the invention, as solvates(e.g., hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds according to the present invention can also be prepared astheir individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomer. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of compounds,dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and can bereadily separated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror thee-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

μL (microliters) Ac (acetyl) atm (atmosphere) ATP (AdenosineTriphophatase) BOC (tert-butyloxycarbonyl) BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride) BSA (Bovine SerumAlbumin) CBZ (benzyloxycarbonyl) CDI (1,1-carbonyldiimidazole) DCC(dicyclohexylcarbodiimide) DCE (dichloroethane) DCM (dichloromethane)DMAP (4-dimethylaminopyridine) DME (1,2-dimethoxyethane) DMF(N,N-dimethylformamide) DMPU (N,N′-dimethylpropyleneurea) DMSO(dimethylsulfoxide) EDCI (ethylcarbodiimide hydrochloride) EDTA(Ethylenediaminetetraacetic acid) Et (ethyl) Et₂O (diethyl ether) EtOAc(ethyl acetate) FMOC (9-fluorenylmethoxycarbonyl) g (grams) h (hours)HOAc or AcOH (acetic acid) HOBT (1-hydroxybenzotriazole) HOSu(N-hydroxysuccinimide) HPLC (high pressure liquid chromatography) Hz(Hertz) i.v. (intravenous) IBCF (isobutyl chloroformate) i-PrOH(isopropanol) L (liters) M (molar) mCPBA (meta-chloroperbenzoic acid) Me(methyl) MeOH (methanol) mg (milligrams) MHz (megahertz) min (minutes)mL (milliliters) mM (millimolar) mmol (millimoles) mol (moles) MOPS(Morpholinepropanesulfonic acid) mp (melting point) NaOAc (sodiumacetate) OMe (methoxy) psi (pounds per square inch) RP (reverse phase)RT (ambient temperature) SPA (Scintillation Proximity Assay) TBAF(tetra-n-butylammonium fluoride) TBS (t-butyldimethylsilyl) tBu(tert-butyl) TEA (triethylamine) TFA (trifluoroacetic acid) TFAA(trifluoroacetic anhydride) THF (tetrahydrofuran) TIPS(triisopropylsilyl) TLC (thin layer chromatography) TMS (trimethylsilyl)TMSE (2-(trimethylsilyl)ethyl) Tr (retention time)

All references to ether or Et₂O are to diethyl ether; and brine refersto a saturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts areexpressed in parts per million (ppm). Coupling constants are in units ofHertz (Hz). Splitting patterns describe apparent multiplicities and aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Waters ZQ LC/MS single quadrupole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E. Merck silica gel plates (60E-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma(St. Louis, Mo.), or may be prepared by methods well known to a personof ordinary skill in the art, following procedures described in suchstandard references as Fieser and Fieser's Reagents for OrganicSynthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd'sChemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier SciencePublishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons,New York, N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed.,John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

The entire disclosures of all documents cited throughout thisapplication are incorporated herein by reference.

Synthetic Schemes for Compounds of the Present Invention

Compounds according to the present invention may be synthesizedaccording to the reaction schemes shown below. Other reaction schemescould be readily devised by those skilled in the art. It should also beappreciated that a variety of different solvents, temperatures and otherreaction conditions can be varied to optimize the yields of thereactions.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

An α-aminoester is condensed with a substituted 2-halo-3-nitropyridine(alternatively with or without solvent or applied heat) followed byreduction of the nitro group and ring closure to give a substitutedpyridopyrazine. Alternatively the nitro reduction and cyclization can becarried out with iron dust in AcOH with heating. Reduction of the methylester at the 7-position is accomplished with lithium aluminum hydride(or other hydride reducint agents) after deprotonation of the amide N—Hto protect the amide.

Nucleophilic substitution of the alcohol with amines is accomplishedafter conversion of the alcohol to the iodide. Other methods of alcoholactivation may be utilized including Mitsunobu conditions among others.

Hydrolysis of a terminal ester is accomplished with lithium hydroxidefollowed by treatment with acid to give a terminal carboxylic acid.Alternatively, other hydrolysis conditions can be utilized, both basicand acidic, including sodium hydroxide, potassium hydroxide,hydrochloric acid and others.

Terminal carboxylic acids are converted to terminal carboxamides throughactivation of the acid with HATU followed by treatment with primary orsecondary amines. Alternatively, other methods exist to convertcarboxylic acids to carboxamides including conversion to an intermediateacid chloride or use of other activation reagents such as EDC, HOBt,EDAC, PyBOP, TATU and others.

Nucleophilic aromatic substitution of a 2-halo-3-nitropyridine withimidazole is carried out followed by reduction of the nitro group.Treatment with CDI forms the pyrazinone.

Deprotection of a Boc group is accomplished by stirring with TFA in DCM.Alternatively, other strong acids and solvents may be used including butnot limited to HCl in EtOAc.

Substituted 4-fluorobenzoic acids are converted to benzamides usingvarious amines and a coupling reagent such as EDC with HOBt.Alternatively, other coupling reagents can be used to form the amide.Subsequent nucleophilic aromatic substitution with piperazine gives therequired substituted 4-piperazinylbenzamides.

Nucleophilic aromatic substitution of aryl fluorides with piperazinegives N-arylpiperazines which can then be protected with a Boc group toallow further functionalization of the aryl substituents. Alternatively,other protecting groups can be used besides Boc.

Substituted 4-fluorobenzonitriles are subjected to nucleophilic aromaticsubstitution with piperazine followed by protection using Boc anhydride.The nitrile is hydrolyzed to the corresponding carboxylic acid which isthen coupled with an amine to give the resulting benzamide. Finally theBoc protecting group is removed by treatment with acid to furnishsubstituted 4-piperazinylbenzamides.

Substituted 4-fluorobenzonitriles are subjected to nucleophilic aromaticsubstitution with Boc-piperazine. The nitrile is hydrolyzed to thecorresponding carboxylic acid which is then coupled with an amine togive the resulting benzamide. Finally the Boc protecting group isremoved to furnish substituted 4-piperazinylbenzamides.

Substituted anilines can be converted to substituted piperazines throughalkylation of the aniline with bis(2-chloroethyl)amine. Alternatively,other halogens or leaving groups can be incorporated in the amine suchas bis(2-bromoethyl)amine or others.

Substituted 4-fluorobenzoates are subjected to nucleophilic aromaticsubstitution with N-Boc piperazine followed by hydrolysis of the esterwith lithium hydroxide to give a protected 4-carboxyphenyl-N-piperazine.Alternatively, other hydrolysis conditions can be utilized, both basicand acidic, including sodium hydroxide, potassium hydroxide,hydrochloric acid and others. Amide formation of the benzoic acid withamines is mediated with coupling reagents such as EDC with HOBt followedby removal of the protecting group with HCl to give the desiredsubstituted 4-benzamidepiperazines. Alternatively, other methods existto convert carboxylic acids to carboxamides including conversion to anintermediate acid chloride or use of other activation reagents such asEDAC, PyBOP, TATU and others.

Chiral components can be separated and purified using any of a varietyof techniques known to those skilled in the art. For example, chiralcomponents can be purified using supercritical fluid chromatography(SFC). In one particular variation, chiral analytical SFC/MS analysesare conducted using a Berger analytical SFC system (AutoChem, Newark,Del.) which consists of a Berger SFC dual pump fluid control module witha Berger FCM 1100/1200 supercritical fluid pump and FCM 1200 modifierfluid pump, a Berger TCM 2000 oven, and an Alcott 718 autosampler. Theintegrated system can be controlled by BI-SFC Chemstation softwareversion 3.4. Detection can be accomplished with a Watrers ZQ 2000detector operated in positive mode with an ESI interface and a scanrange from 200-800 Da with 0.5 second per scan. Chromatographicseparations can be performed on a ChiralPak AD-H, ChiralPak AS-H,ChiralCel OD-H, or ChiralCel OJ-H column (5μ, 4.6×250 mm; ChiralTechnologies, Inc. West Chester, Pa.) with 10 to 40% methanol as themodifier and with or without ammonium acetate (10 mM). Any of a varietyof flow rates can be utilized including, for example, 1.5 or 3.5 mL/minwith an inlet pressure set at 100 bar. Additionally, a variety of sampleinjection conditions can be used including, for example, sampleinjections of either 5 or 10 μLin methanol at 0.1 mg/mL inconcentration.

In another variation, preparative chiral separations are performed usinga Berger MultiGram II SFC purification system. For example, samples canbe loaded onto a ChiralPak AD column (21×250 mm, 10μ). In particularvariations, the flow rate for separation can be 70 mL/min, the injectionvolume up to 2 mL, and the inlet pressure set at 130 bar. Stackedinjections can be applied to increase the efficiency.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Descriptions of the syntheses of particular compounds according to thepresent invention based on the above reaction scheme are set forthherein.

Examples of PARP Inhibitors

The present invention is further exemplified, but not limited by, thefollowing examples that describe the synthesis of particular compoundsaccording to the invention.

Compound 1:(S)-3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 1A: (S)-Methyl6-(2-(methoxycarbonyl)pyrrolidin-1-yl)-5-nitronicotinate: (S)-Methylpyrrolidine-2-carboxylate (6.56 g, 50.8 mmol) was added to methyl6-chloro-5-nitronicotinate (5.00 g, 23.1 mmol) and the reaction mixturewas stirred at 90° C. for 10 min (exothermic reaction). It as cooled toroom temperature, diluted with EtOAc (10 mL) and purified using flashcolumn chromatography on silica gel (20-30% EtOAc in hexanes) to affordthe title compound as a yellow oil (6.70 g, 94%). [M+H] calc'd forC₁₃H₁₅N₃O₆, 310. found, 310.

Compound 1B: (S)-methyl6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate:(S)-Methyl 6-(2-(methoxycarbonyl)pyrrolidin-1-yl)-5-nitronicotinate(1.45 g, 46.9 mmol) and triphenyl phosphite (5.00 mg, 0.0161 mmol) weredissolved in dichloromethane (12 mL). Ammonium metavanadate (50 mg,0.427 mmol) and Pt/C (5% wt., 200 mg) were added and the reactionmixture was stirred under hydrogen (80 psi) for 5 h. The reactionmixture was filtered through a small plug of celite and the precipitatewas washed multiple times with hot dichloromethane until it was freefrom white precipitate. The filtrate was concentrated in vacuo andcrystallized with ethyl ether (15 mL). The resulting solid was filteredoff and dried in vacuum to afford the title compound as an off-whitesolid (0.930 g, 80%). [M+H] calc'd for C₁₂H₁₃N₃O₃, 248; found, 248.

Compound 1C:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one:(S)-methyl6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate(3.00 g, 10.5 mmol) was suspended in THF and sodium hydride (60%suspension in mineral oil, 0.712 g, 17.8 mmol) was added under nitrogenatmosphere. The reaction mixture was stirred at room temperature for 1 hand cooled to −78° C. LiAlH₄ (2M in THF, 12.5 mL, 25 mmol) was addeddropwise over 5 min and the reaction mixture was allowed to warm to −40°C. and kept at −40-(−20)° C. for 3 h. The reaction mixture was cooled to−60° C. and quenched with MeOH, water and TFA until a clear mixtureresulted. This was purified using HPLC (1-30% acetnitrile in water, TFAbuffered). The fractions containing product were concentrated in vacuoand crystallized with ethyl ether. The solid was filtered and dried invacuum to afford the title compound as a grey solid (2.60 g, 74%, TFAsalt). [M+H] calc'd for C₁₁H₁₃N₃O₂, 220; found, 220.

Compound 1:(S)-3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(200 mg, 0.912 mmol), 1-(4-chlorophenyl)piperazine hydrochloride (200mg, 0.858 mmol), N,N-diisopropylethylamine (DIPEA; 0.50 mL), and(cyanomethyl)trimethylphosphonium iodide (220 mg, 1.08 mmol) weresuspended in propionitrile (2 mL) and heated in a closed vial at 90° C.for 4 h. The reaction mixture was diluted with MeOH (2 mL) and purifiedusing preparative scale HPLC (45-95% acetonitrile in water, bufferedwith NH₄HCO₃). The fractions containing product were concentrated invacuo and diluted with water (5 mL). The resulting precipitate wasfiltered and dried in vacuum to afford the title compound as anoff-white solid (135 mg, 40%). ¹H NMR (DMSO-d₆) δ (ppm): 10.43 (s, 1H),7.61 (d, J=1.8 Hz, 1H), 7.21 (d, J=8.8 Hz, 2H), 6.98 (d, J=1.8 Hz, 1H),6.92 (d, J=9.1 Hz, 2H), 3.91-4.06 (m, 1H), 3.51-3.66 (m, 1H), 3.37-3.47(m, 1H), 3.10 (br. s., 4H), 2.46 (d, J=4.3 Hz, 4H), 2.09-2.26 (m, 1H),1.80-2.03 (m, 3H); [M+H] calc'd for C₂₁H₂₄ClN₅O, 398; found, 398.melting point 265-268° C.

Compound 2:(S)-3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 2 was prepared using a procedure analogous to that described inconnection with compound 1, except that4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride was usedinstead of 1-(4-chlorophenyl)piperazine hydrochloride. ¹H NMR(CHLOROFORM-d) δ (ppm): 7.77 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.29-7.33(m, 2H), 7.26-7.29 (m, 2H), 7.01 (d, J=1.8 Hz, 1H), 6.01-6.08 (m, 1H),4.07 (dd, J=9.2, 6.4 Hz, 1H), 3.72-3.83 (m, 1H), 3.57-3.66 (m, 1H),3.44-3.55 (m, 2H), 3.15 (q, J=2.8 Hz, 2H), 2.65-2.76 (m, 2H), 2.47-2.57(m, 2H), 2.34-2.46 (m, 1H), 1.94-2.26 (m, 3H): [M+H] calc'd forC₂₂H₂₃ClN₄O, 395; found, 395. melting point 234-235° C.

Compound 3:(S)-3-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 3 was prepared using a procedure analogous to that described inconnection with compound 1, except that 4-(4-chlorophenyl)piperidinehydrochloride was used instead of 1-(4-chlorophenyl)piperazinehydrochloride. ¹H NMR(CHLOROFORM-d) δ (ppm): 7.92 (br. s., 1H), 7.74 (d,J=1.5 Hz, 1H), 7.26 (d, J=8.3 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 6.99 (d,J=1.5 Hz, 1H), 4.07 (dd, J=9.5, 6.4 Hz, 1H), 3.69-3.82 (m, 1H),3.54-3.66 (m, 1H), 3.33-3.49 (m, 2H), 3.00 (d, J=11.4 Hz, 2H), 2.33-2.55(m, 2H), 1.95-2.25 (m, 5H), 1.74-1.85 (m, 3H); [M+H] calc'd forC₂₂H₂₅ClN₄O, 397; found, 397.

Compound 4:(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

Compound 4 was prepared using a procedure analogous to that described inconnection with compound 1, except that 4-(piperazin-1-yl)benzonitrilewas used instead of 1-(4-chlorophenyl)piperazine hydrochloride. ¹H NMR(DMSO-d₆) δ (ppm): 10.44 (s, 1H), 7.59 (dd, J=16.9, 5.3 Hz, 3H), 6.99(dd, J=9.3, 5.3 Hz, 3H), 3.91-4.07 (m, 1H), 3.51-3.65 (m, 1H), 3.31-3.46(m, 7H), 2.37-2.47 (m, 4H), 2.10-2.25 (m, 1H), 1.82-2.01 (m, 3H); [M+H]calc'd for C₂₂H₂₄N₆O, 389; found, 389. melting point 252° C.

Compound 5:(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinonitrile

Compound 5 was prepared using a procedure analogous to that described inconnection with compound 1, except that6-(piperazin-1-yl)nicotinonitrile was used instead of1-(4-chlorophenyl)piperazine hydrochloride. ¹H NMR (DMSO-d₆) δ (ppm):10.44 (s, 1H), 8.47 (d, J=2.3 Hz, 1H), 7.84 (dd, J=9.1, 2.3 Hz, 1H),7.60 (d, J=1.5 Hz, 1H), 6.98 (d, J=1.8 Hz, 1H), 6.91 (d, J=9.1 Hz, 1H),3.92-4.06 (m, 1H), 3.57-3.71 (m, 5H), 3.27-3.48 (m, 3H), 2.40 (t, J=4.5Hz, 4H), 2.10-2.24 (m, 1H), 1.81-2.01 (m, 3H); [M+H] calc'd forC₂₁H₂₃N₇O, 390. found, 390. melting point 252-256° C.

Compound 6:(S)-N-methyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide

Compound 6A: (S)-ethyl6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinate:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(233 mg, 1.06 mmol), ethyl 6-(piperazin-1-yl)nicotinate (270 mg, 0.1.15mmol), DIPEA (0.80 mL), and (cyanomethyl)trimethylphosphonium iodide(369 mg, 01.82 mmol) were suspended in propionitrile (3 mL) and heatedin a closed vial at 90° C. for 5 h. The mixture was cooled, diluted witha solution of K₂CO₃ (2.50 g) in water (15 mL) and extracted withdichloromethane (2×10 mL). The combined organic extracts were dried(MgSO4) and concentrated in vacuo. The resulting oil was crystallizedwith ethyl ether-ethanol (10:1, 22 mL) to afford the title compounds asa tan solid (0.355 mg, 77%). [M+H] calc'd for C₂₃H₂₈N₆O₃, 437; found,437.

Compound 6B:(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinicacid: (S)-ethyl6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinate(0.355 mg, 0.813 mmol) was suspended in dioxane (4 mL) and treated withLiOH (1N, 4.00 mL, 4.00 mmol). The resulting solution was stirred atroom temperature for 3 h and concentrated in vacuo until most of theorganic solvent was removed. The solution was acidified with HCl (4.5N)to pH=3 and the resulting precipitate was filtered off, washed withethyl ether (5 mL) and dried in vacuum to afford the title compound as abrown solid (0.260 g, 78%). [M+H] calc'd for C₂₁H₂₄N₆O₃, 409; found,409.

Compound 6:(S)-N-methyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide:(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinicacid (100 mg, 0.245 mmol) was suspended in DMF (1.5 mL) and DIPEA (0.3mL) was added followed by methylamine hydrochloride (27 mg, 0.400 mmol)and HATU (200 mg, 0.526 mmol). The reaction mixture was stirred atambient temperature for 4 h and diluted with MeOH (2 mL). The solutionwas purified using HPCL (25-95% acetonitrile in water, NH₄HCO₃buffered). The fractions were concentrated in vacuo and the resultingresidue was crystallized with MeOH-water (1:5, 15 mL) to afford thetitle compound as an off-white solid (52.3 mg, 51%). ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 1.80-2.03 (m, 3 H) 2.09-2.25 (m, 1 H) 2.41 (br. s., 4H) 2.74 (d, J=4.29 Hz, 3 H) 3.34-3.44 (m, 3 H) 3.46-3.64 (m, 5 H)3.92-4.05 (m, 1 H) 6.82 (d, J=9.09 Hz, 1 H) 6.99 (d, 1 H) 6.93-7.04 (m,1 H) 7.61 (s, 1 H) 7.91 (dd, J=8.97, 2.15 Hz, 1 H) 8.17-8.23 (m, 1H)8.56 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C₂₂H₂₇N₇O₂,422; found, 422.

Compound 7:(S)-N-ethyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide

(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinicacid (87 mg, 0.213 mmol) and ethanamine hydrochloride (17.4 mg, 0.213mmol) were suspended in DMF (1.065 mL) and treated with DIPEA (0.186 mL,1.065 mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture wasstirred at room temperature for 3 h and purified using HPLC (10-95%acetonitrile in water, NH₄HCO₃ buffered) to afford(S)-N-ethyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide(26.4 mg, 0.061 mmol, 28.5% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 1.09 (t, J=7.20 Hz, 3 H) 1.82-2.02 (m, 3 H) 2.18(d, J=2.27 Hz, 1 H) 2.41 (t, J=4.80 Hz, 5 H) 3.20-3.29 (m, 2 H)3.34-3.44 (m, 3 H) 3.51-3.63 (m, 5 H) 3.95-4.03 (m, 1 H) 6.82 (d, J=9.09Hz, 1 H) 6.99 (d, J=1.77 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 7.93 (dd,J=9.09, 2.53 Hz, 1 H) 8.23 (t, J=5.31 Hz, 1 H) 8.57 (d, J=2.27 Hz, 1 H)10.44 (s, 1 H); [M+H] calc'd for C₂₃H₂₉N₇O₂, 422; found, 422.

Compound 8:(S)-N-cyclopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide

(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinicacid (87 mg, 0.213 mmol) and cyclopropanamine (18.24 mg, 0.319 mmol)were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.065mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture wasstirred at room temperature for 3 h and purified using HPLC (10-95%acetonitrile in water, NH₄HCO₃ buffered) to afford(S)-N-cyclopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide(70.3 mg, 0.157 mmol, 73.7% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d6) δ (ppm): 0.49-0.56 (m, 2H) 0.62-0.70 (m, 2 H) 1.82-2.02(m, 3 H) 2.11-2.22 (m, 1 H) 2.40 (t, J=4.93 Hz, 4 H) 2.78 (tq, J=7.34,3.86 Hz, 1H) 3.34 (br. s., 2 H) 3.36-3.44 (m, 1 H) 3.49-3.64 (m, 5 H)3.94-4.03 (m, 1 H) 6.81 (d, J=8.59 Hz, 1 H) 6.98 (d, J=1.77 Hz, 1 H)7.61 (d, J=1.77 Hz, 1 H) 7.90 (dd, J=9.09, 2.53 Hz, 1H) 8.20 (d, J=4.04Hz, 1 H) 8.54 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd forC₂₄H₂₉N₇O₂, 448; found, 448.

Compound 9:(S)-N-isopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide

(S)-6-(4((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinicacid (87.0 mg, 0.213 mmol) and propan-2-amine (18.89 mg, 0.319 mmol)were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.065mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (162 mg, 0.426 mmol). The reaction mixture wasstirred at room temperature for 3 h and purified using HPLC (10-95%acetonitrile in water, NH₄HCO₃ buffered) to afford(S)-N-isopropyl-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide(62.1 mg, 0.138 mmol, 64.9% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d6) δ (ppm): 1.13 (d, J=6.57 Hz, 6 H) 1.84-2.01 (m, 3 H)2.12-2.22 (m, 1 H) 2.41 (d, J=4.29 Hz, 4 H) 3.36-3.47 (m, 1H) 3.49-3.64(m, 5 H) 3.95-4.10 (m, 2 H) 6.81 (d, J=8.84 Hz, 1 H) 6.99 (d, J=2.02 Hz,1 H) 7.61 (d, J=1.77 Hz, 1 H) 7.94 (dd, J=9.09, 2.53 Hz, 1 H) 7.97 (d,J=7.83 Hz, 1 H) 8.57 (d, J=2.53 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'dfor C₂₄H₃₁N₇O₂, 450; found, 450.

Compound 10:(S)-N-ethyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 10A: (S)-ethyl4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(187 mg, 0.854 mmol), ethyl 4-(piperazin-1-yl)benzoate (200 mg, 0.854mmol), (cyanomethyl)trimethylphosphonium iodide (311 mg, 1.280 mmol) andN,N-diisopropylethylamine (0.745 ml, 4.27 mmol) were suspended inpropionitrile (2 ml) and heated in a closed vial at 90° C. for 2 h. Thereaction mixture became a clear dark brown solution. The mixture wascooled to room temperature, diluted with MeOH (2 mL), filtered, thesolids retained, and purified using preparative HPLC. The fractionscontaining product were concentrated in vacuo and crystallized fromwater (3 mL). The precipitate was filtered and dried in vacuum to affordthe product as a light brown solid (18.3 mg). The solid from the earlierfiltration was recrystallized from ether-MeOH (10 mL, 5:1). The combinedproducts were dried in vacuum to afford (S)-ethyl4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate(283 mg, 0.650 mmol, 76% yield) as a brownish solid. [M+H] calc'd forC₂₄H₂₉N₅O₃, 436; found, 436. melting point 242° C.

Compound 10B:(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid: (S)-ethyl4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate(280 mg, 0.643 mmol) was suspended in 1,4-Dioxane (3.22 mL) and treatedwith 1N LiOH (3.215 mL, 3.22 mmol). The reaction mixture was stirred atroom temperature for 23 h. The reaction mixture was concentrated invacuo until most of the dioxane was gone and acidified with HCl (4.5 N)until a thick precipitate resulted. It was filtered off, washed withwater and dried in vacuum to afford(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (225 mg, 0.552 mmol, 86% yield) as a brown solid. [M+H] calc'd forC₂₂H₂₅N₅O₃, 408; found, 408.

Compound 10:(S)-N-ethyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (75.0 mg, 0.184 mmol) was suspended in DMF (1.0 mL) and DIPEA (0.15mL) was added followed by ethylamine (30 mg, 0.665 mmol) and HATU (85.0mg, 0.224 mmol). The reaction mixture was stirred at ambient temperaturefor 2 h and another portion of HATU (60.0 mg, 0.158 mmol) was added. Thereaction mixture was stirred overnight and purified using HPCL (10-75%acetonitrile in water, NH₄HCO₃ buffered). The fractions wereconcentrated in vacuo and the resulting residue was crystallized withMeOH-water (1:10, 5 mL) to afford the title compound as a light greensolid (24.0 mg, 30%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 1.09 (t, J=7.20Hz, 3 H) 1.85-2.01 (m, 3 H) 2.18 (dt, J=5.37, 2.75 Hz, 1 H) 2.43-2.48(m, 4 H) 3.18-3.28 (m, 6 H) 3.35 (s, 2 H) 3.37-3.45 (m, 1 H) 3.54-3.67(m, 1 H) 3.94-4.05 (m, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 6.99 (d, J=2.02 Hz,1 H) 7.62 (d, J=2.02 Hz, 1 H) 7.71 (d, J=9.09 Hz, 2 H) 8.17 (t, J=5.56Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C₂₄H₃₀N₆O₂, 435; found, 435.

Compound 10C: N-ethyl-4-fluorobenzamide: To a solution of ethylamine(69.4 mL, 139 mmol) and triethylamine (21.10 mL, 151 mmol) in DCM(Volume: 150 mL) was added p-Fluorobenzoyl chloride (15.13 mL, 126 mmol)at 0° C. The reaction was stirred at 0° C. for 1 hr and then warmedslowly to room temperature. The reaction mixture was diluted with water.The layers were separated and the organic layer was washed with brine,dried over MgSO₄, filtered, and the organic phase stripped to drynessvia rotary evaporation. The organic extract was dried in vacuo toprovide N-ethyl-4-fluorobenzamide (21 g, 100% yield) as a tan solid.

Compound 10D: N-ethyl-4-(piperazin-1-yl)benzamide: UsingN-ethyl-4-fluorobenzamide in the general procedure for nucleophilicaromatic substitution reactions with piperazine, the title compound wasobtained (77% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.10 (t, J=7.07 Hz, 3 H) 2.25 (br. s., 1 H) 2.76-2.86 (m, 4 H) 3.09-3.18(m, 4 H) 3.21-3.28 (m, 2 H) 6.90 (m, J=8.84 Hz, 2 H) 7.67-7.75 (m, 2 H)8.11 (t, J=5.31 Hz, 1 H). ESI-MS: m/z 234.2 (M+H)⁺. mp=131.3-134.4° C.

Compound 10:(S)-N-ethyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:To a suspension of(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(0.8 g, 3.65 mmol)) in propiononitrile (Volume: 27.4 ml) was added(cyanomethyl)trimethylphosphonium iodide (1.064 g, 4.38 mmol),N-ethyl-4-(piperazin-1-yl)benzamide (0.851 g, 3.65 mmol) and DIEA (1.912ml, 10.95 mmol). The vial was heated to 90° C. for 16 hours. The crudereaction was cooled to RT, DMSO (1 ml) was added, and the mixture waspurified via HPLC (55-90, basic) to give the product as a white solid.

Compound 11:(S)-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (87 mg, 0.214 mmol) and methanamine hydrochloride (21.62 mg, 0.320mmol) were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml,1.068 mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture wasstirred at room temperature for 23 h and purified using HPLC (25-95%acetonitrile in water, NH₄HCO₃ buffered) to afford(S)-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(42.4 mg, 0.101 mmol, 47.2% yield) as a light yellow solid. ¹H NMR (400MHz, DMSO-d6) δ (ppm): 1.83-2.01 (m, 3 H) 2.11-2.25 (m, 1 H) 2.39-2.48(m, 4 H) 2.73 (d, J=4.55 Hz, 3 H) 3.13-3.27 (m, 4 H) 3.34-3.44 (m, 3 H)3.52-3.64 (m, 1 H) 3.96-4.02 (m, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 6.98 (d,J=2.02 Hz, 1 H) 7.62 (d, J=1.77 Hz, 1 H) 7.69 (d, J=9.09 Hz, 2 H) 8.13(q, J=4.29 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C₂₃H₂₈N₆O₂, 421;found, 421.

Compound 11A: N-methyl-4-(piperazin-1-yl)benzamide: To a solution of4-fluoro-N-methylbenzamide (6 g, 39.2 mmol) in DMSO (Volume: 24.0 mL)was added piperazine (16.87 g, 196 mmol) at 23° C. The reaction wasstirred at 120° C. for 68 hr. The reaction mixture was poured into ice(261 g) and the reaction vessel was rinsed with H2O (˜50 mL). Next,celite (30 g) was added to aid the filtration. The resulting suspensionwas warmed to 100° C., cooled to ˜40° C., filtered, and rinsed with warmH20 (4×50 mL). The resulting solid was dried in vacuo. The filtrate wasstirred at room temperature overnight affording a suspension. Thesuspension was filtered, rinsed with H₂O (3×25 mL), and the resultingsolid was dried in vacuo. The cloudy filtrate was filtered once againthrough a medium fitted funnel and rinsed with H2O (3×10 mL). Added NaCl(200.1 g) to the filtrate, cooled on ice, filtered, rinsed with cold H2O(3×25 mL), and dried the resulting solid in vacuo. Re-suspended thepurified product in H2O (30 mL), stirred for 30 min at 23° C., filtered,rinsed with H2O (3×5 mL), and dried the resulting solid in vacuo. Thepurified product was re-suspended in ACN (25 mL), agitated for 10 min,and dried in vacuo. This procedure was repeated three times to provideN-methyl-4-(piperazin-1-yl)benzamide (5.64 g, 25.7 mmol, 65.7% yield) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.29 (br. s., 1H) 2.74(d, J=4.55 Hz, 3 H) 2.77-2.86 (m, 4 H) 3.08-3.18 (m, 4 H) 6.91 (m, 2 H)7.69 (m, 2 H) 8.13 (q, J=4.04 Hz, 1 H). ESI-MS: m/z 220.2 (M+H)⁺.mp=153.9-156.5° C.

Compound 11:(S)-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(1.500 g, 6.84 mmol), N-methyl-4-(piperazin-1-yl)benzamide (1.500 g,6.84 mmol), (cyanomethyl)trimethylphosphonium iodide (2.494 g, 10.26mmol) and N,N-diisopropylethylamine (5.97 ml, 34.2 mmol) were suspendedin propiononitrile (Volume: 27.4 ml) and heated in a closed vial at 90°C. The crude reaction was cooled to RT, DMSO (1 ml) was added, and themixture was purified via HPLC (55-90, basic) to give the product as awhite solid.

Compound 12:(S)-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (87.0 mg, 0.214 mmol) and propan-2-amine (18.93 mg, 0.320 mmol)were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture wasstirred at room temperature for 3 h and purified using HPLC (25-95%acetonitrile in water, NH₄HCO₃ buffered) to afford(S)-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(39.6 mg, 0.088 mmol, 41.3% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d6) δ (ppm): 1.13 (d, J=6.57 Hz, 6 H) 1.85-2.00 (m, 3 H)2.11-2.24 (m, 1 H) 2.41-2.48 (m, 4 H) 3.17-3.27 (m, 4 H) 3.34-3.44 (m, 3H) 3.53-3.65 (m, 1 H) 3.93-4.13 (m, 2 H) 6.91 (d, J=9.09 Hz, 2 H) 6.99(d, J=2.02 Hz, 1 H) 7.62 (d, J=2.02 Hz, 1 H) 7.72 (d, J=9.09 Hz, 2 H)7.89 (d, J=7.83 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C₂₅H₃₂N₆O₂,449; found, 449.

Compound 13:(S)-N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (87 mg, 0.214 mmol) and cyclopropanamine (18.29 mg, 0.320 mmol)were suspended in DMF (1 ml) and treated with DIPEA (0.186 ml, 1.068mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (162 mg, 0.427 mmol). The reaction mixture wasstirred at room temperature for 3 h and purified using HPLC (25-95%acetonitrile in water, NH₄HCO₃ buffered) to afford(S)-N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(43.0 mg, 0.096 mmol, 45.1% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d6) δ (ppm): 0.46-0.59 (m, 2 H) 0.59-0.71 (m, 2 H) 1.82-2.02(m, 3 H) 2.10-2.25 (m, 1 H) 2.46 (br. s., 4 H) 2.74-2.83 (m, 1 H) 3.21(br. s., 4 H) 3.34-3.46 (m, 3 H) 3.53-3.64 (m, 1 H) 3.94-4.02 (m, 1 H)6.91 (d, J=8.84 Hz, 2 H) 6.98 (d, J=1.77 Hz, 1 H) 7.61 (d, J=1.26 Hz, 1H) 7.68 (d, J=8.84 Hz, 2 H) 8.13 (d, J=4.04 Hz, 1 H) 10.44 (s, 1H);[M+H] calc'd for C₂₅H₃₀N₆O₂, 447; found, 447. melting point 265-268° C.

Compound 13A: N-cyclopropyl-4-(piperazin-1-yl)benzamide: UsingN-cyclopropyl-4-fluorobenzamide in the general procedure fornucleophilic aromatic substitution reactions, the title compound wasobtained (15% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.47-0.58 (m, 2 H) 0.58-0.73 (m, 2 H) 2.28 (br. s., 1 H) 2.70-2.88(m, 5 H) 3.04-3.21 (m, 4 H) 6.90 (m, J=9.09 Hz, 2 H) 7.69 (m, J=8.84 Hz,2 H) 8.12 (d, J=3.79 Hz, 1 H). ESI-MS: m/z 246.2 (M+H)⁺. mp=175.1-177.2°C.

Compound 13:(S)-N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(300 mg, 1.368 mmol), N-cyclopropyl-4-(piperazin-1-yl)benzamide (336 mg,1.368 mmol), (cyanomethyl)trimethylphosphonium iodide (499 mg, 2.053mmol) and N,N-diisopropylethylamine (1195 μl, 6.84 mmol) were suspendedin propionitrile (Volume: 4109 μl) and heated in a closed vial at 120°C. for 2 h. The reaction mixture became a dark brown solution. It wascooled to room temperature, concentrated in vacuo, dissolved in DMSO (2mL) and purified using HPLC (NH₄HCO₃ buffered, 20-70% ACN in water). Thefractions were concentrated in vacuo and the resulting solid wasrecrystallized from water-MeOH (1:1, 15 mL), and then fromMeOH:EtOH:water (1:1:1, 10 mL), washed with water (3 mL) and dried invacuum to give a light green solid.

Compound 14:(S)-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(150 mg, 0.684 mmol), 3-fluoro-4-(piperazin-1-yl)benzonitrile (140 mg,0.684 mmol), (cyanomethyl)trimethylphosphonium iodide (249 mg, 1.026mmol) and N,N-diisopropylethylamine (0.597 ml, 3.42 mmol) were suspendedin propionitrile (2 ml) and heated in a closed vial at 90° C. for 2 h.The reaction mixture became a clear dark brown solution. It was cooledto room temperature, diluted with DMSO (2 mL) and purified usingpreparative HPLC (25-95% acetonitrile in water, NH₄HCO₃ buffered). Thefractions containing product were concentrated in vacuo and crystallizedwith water (3 mL). The precipitate was filtered and dried in vacuum toafford(S)-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile(60.2 mg, 0.148 mmol, 21.65% yield) as a light brown solid. ¹H NMR (400MHz, DMSO-d6) δ (ppm): 1.83-2.03 (m, 3 H) 2.11-2.24 (m, 1 H) 2.44-2.49(m, 4 H) 3.07-3.22 (m, 4 H) 3.34-3.42 (m, 3 H) 3.53-3.65 (m, 1 H)3.93-4.03 (m, 1 H) 6.97 (d, J=2.02 Hz, 1 H) 7.11 (t, J=8.72 Hz, 1 H)7.56 (dd, J=8.46, 1.64 Hz, 1 H) 7.61 (d, J=2.02 Hz, 1 H) 7.69 (dd,J=13.39, 2.02 Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C₂₂H₂₃FN₆O, 407;found, 407. melting point 226° C.

Compound 15:(S)-3-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(150 mg, 0.684 mmol), 1-(2,4-difluorophenyl)piperazine (136 mg, 0.684mmol), (cyanomethyl)trimethylphosphonium iodide (249 mg, 1.026 mmol) andN,N-diisopropylethylamine (0.597 ml, 3.42 mmol) were suspended inpropionitrile (2 ml) and heated in a closed vial at 90° C. for 2 h. Thereaction mixture became a clear dark brown solution. It was cooled toroom temperature, diluted with DMSO (2 mL) and purified usingpreparative HPLC (25-95% acetonitrile in water, NH₄HCO₃ buffered). Thefractions containing product were concentrated in vacuo and crystallizedfrom water (3 mL). The precipitate was filtered and dried in vacuum toafford(S)-3-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(63.2 mg, 0.158 mmol, 23.13% yield) as a light brown solid. ¹H NMR (400MHz, DMSO-d6) δ (ppm): 1.84-2.03 (m, 3 H) 2.09-2.26 (m, 1 H) 2.41-2.49(m, 4 H) 2.88-2.99 (m, 4 H) 3.34-3.43 (m, 3 H) 3.54-3.63 (m, 1 H)3.94-4.02 (m, 1 H) 6.93-7.09 (m, 3 H) 7.18 (ddd, J=12.44, 9.16, 2.91 Hz,1 H) 7.61 (d, J=1.77 Hz, 1H) 10.44 (s, 1 H); [M+H] calc'd forC₂₁H₂₃F₂N₅O, 400; found, 400.

Compound 16:(S)-3-chloro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

Compound 16A: tert-Butyl4-(2-chloro-4-cyanophenyl)piperazine-1-carboxylate: Tert-Butylpiperazine-1-carboxylate (0.931 g, 5 mmol) and3-chloro-4-fluorobenzonitrile (0.785 g, 5.00 mmol) were combined, K₂CO₃(0.898 g, 6.50 mmol) was added and the reaction mixture was stirred at90° C. for 1 d. The mixture was triturated with ethyl acetate (3×5 mL)and the combined organic extracts were filtered. This was concentrateddown to about 5-10 mL and subjected to flash column chromatography onsilica gel (120 g SiO₂, hexanes:ethyl acetate 1:0 to 4:1) to affordtert-butyl 4-(2-chloro-4-cyanophenyl)piperazine-1-carboxylate (1.264 g,3.93 mmol, 79% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ(ppm): 1.42 (s, 9 H) 3.00-3.09 (m, 4 H) 3.42-3.53 (m, 4 H) 7.25 (d,J=8.59 Hz, 1 H) 7.77 (dd, J=8.34, 2.02 Hz, 1 H) 7.97 (d, J=2.02 Hz, 1H); [M+H] calc'd for C₁₆H₂₀ClN₃O₂, 322; found, 322.

Compound 16B: 3-chloro-4-(piperazin-1-yl)benzonitrile hydrochloride:Tert-Butyl 4-(2-chloro-4-cyanophenyl)piperazine-1-carboxylate (0.322 g,1 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirred for 30min. The thick white precipitate that formed was diluted with ethylether (10 mL) and stirred until a fine suspension resulted. Theprecipitate was filtered under nitrogen and dried in vacuum to afford3-chloro-4-(piperazin-1-yl)benzonitrile hydrochloride (0.242 g, 0.937mmol, 94% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ (ppm):3.14-3.29 (m, 4 H) 3.27-3.38 (m, 4 H) 7.33 (d, J=8.34 Hz, 1 H) 7.80 (dd,J=8.46, 1.89 Hz, 1 H) 8.02 (d, J=2.02 Hz, 1 H) 9.37 (br. s., 2 H); 4 H)7.25 (d, J=8.59 Hz, 1 H) 7.77 (dd, J=8.34, 2.02 Hz, 1 H) 7.97 (d, J=2.02Hz, 1 H); [M+H] calc'd for C₁₁H₁₂ClN₃, 222; found, 222.

Compound 16:(S)-3-chloro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), 3-chloro-4-(piperazin-1-yl)benzonitrilehydrochloride (118 mg, 0.456 mmol), (cyanomethyl)trimethylphosphoniumiodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml,2.281 mmol) were suspended in propionitrile (2 ml) and heated in aclosed vial at 90° C. for 2 h. The reaction mixture became a dark brownsolution. It was cooled to room temperature, concentrated in vacuo andpurified using flash column chromatography on silica gel (80 g SiO₂,dichloromethane-methanol 100:0-95:5). The resulting solid was suspendedin ether (7 mL), stirred until a fine suspension resulted, filtered andthe solid was dried in vacuum to afford(S)-3-chloro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile(135.4 mg, 0.320 mmol, 70.2% yield) as a light brown solid. ¹H NMR (400MHz, DMSO-d6) δ (ppm): 1.80-2.03 (m, 3 H) 2.10-2.25 (m, 1 H) 2.39-2.61(m, 4 H) 2.94-3.19 (m, 4 H) 3.35-3.46 (m, 3 H) 3.51-3.65 (m, 1 H)3.91-4.05 (m, 1 H) 6.97 (d, J=1.77 Hz, 1 H) 7.22 (d, J=8.59 Hz, 1 H)7.62 (d, J=1.52 Hz, 1 H) 7.74 (dd, J=8.46, 1.89 Hz, 1 H) 7.93 (d, J=1.77Hz, 1 H) 10.44 (s, 1 H); [M+H] calc'd for C₂₂H₂₃ClN₆O, 423; found, 423.melting point 213-215° C.

Compound 17:(S)-2,5-difluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

Compound 17 was prepared using a procedure analogous to that describedin connection with compound 16, except that 2,4,5-trifluorobenzonitrilewas used instead of 3-chloro-4-fluorobenzonitrile. ¹H NMR (400 MHz,DMSO-d6) δ (ppm): 1.81-2.01 (m, 3 H) 2.11-2.25 (m, 1 H) 2.47 (br. s., 4H) 3.22 (br. s., 4 H) 3.34-3.44 (m, 3 H) 3.52-3.65 (m, 1 H) 3.92-4.05(m, 1 H) 6.97 (d, J=1.52 Hz, 1 H) 7.08 (dd, J=12.00, 7.20 Hz, 1 H) 7.61(d, J=1.52 Hz, 1 H) 7.77 (dd, J=13.14, 6.32 Hz, 1 H) 10.45 (s, 1 H);[M+H] calc'd for C₂₂H₂₂F₂N₆O, 425; found, 425. melting point 224-227° C.

Compound 18:(S)-2,3-difluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

Compound 18 was prepared using a procedure analogous to that describedin connection with compound 16, except that 2,3,4-trifluorobenzonitrilewas used instead of 3-chloro-4-fluorobenzonitrile. ¹H NMR (400 MHz,DMSO-d6) δ (ppm): 1.82-2.03 (m, 3 H) 2.09-2.28 (m, 1 H) 2.38-2.49 (m, 4H) 3.24 (br. s., 4 H) 3.34-3.45 (m, 3 H) 3.52-3.63 (m, 1 H) 3.93-4.03(m, 1 H) 6.88-6.99 (m, 2 H) 7.52-7.63 (m, 2 H) 10.45 (s, 1 H); [M+H]calc'd for C₂₂H₂₂F₂N₆O, 425; found, 425.

Compound 19:(S)-2,6-difluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

Compound 19 was prepared using a procedure analogous to that describedin connection with compound 16, except that 2,4,6-trifluorobenzonitrilewas used instead of 3-chloro-4-fluorobenzonitrile. ¹H NMR (400 MHz,DMSO-d6) δ (ppm): 1.83-2.04 (m, 3 H) 2.09-2.26 (m, 1 H) 2.33-2.47 (m, 4H) 3.35 (s, 2 H) 3.37-3.49 (m, 5 H) 3.53-3.66 (m, 1 H) 3.94-4.06 (m, 1H) 6.86 (d, J=12.63 Hz, 2 H) 6.97 (d, J=1.77 Hz, 1 H) 7.61 (d, J=1.52Hz, 1 H) 10.45 (s, 1 H); [M+H] calc'd for C₂₂H₂₂F₂N₆O, 425; found, 425.

Compound 20:(S)-3,5-difluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

Compound 20 was prepared using a procedure analogous to that describedin connection with compound 16, except that 3,4,5-trifluorobenzonitrilewas used instead of 3-chloro-4-fluorobenzonitrile. ¹H NMR (400 MHz,DMSO-d6) δ (ppm): 1.81-2.04 (m, 3 H) 2.11-2.25 (m, 1 H) 2.43 (br. s., 4H) 3.23 (br. s., 4 H) 3.34-3.47 (m, 3 H) 3.53-3.64 (m, 1 H) 3.94-4.01(m, 1 H) 6.98 (d, J=1.52 Hz, 1 H) 7.61 (d, J=1.77 Hz, 1 H) 7.62-7.72 (m,2 H) 10.43 (s, 1 H); [M+H] calc'd for C₂₂H₂₂F₂N₆O, 425; found, 425.

Compound 21:(S)-2-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

Compound 21 was prepared using a procedure analogous to that describedin connection with compound 16, except that 2,4-difluorobenzonitrile wasused instead of 3-chloro-4-fluorobenzonitrile. ¹H NMR (400 MHz, DMSO-d6)δ (ppm): 1.84-2.01 (m, 3 H) 2.10-2.23 (m, 1 H) 2.36-2.47 (m, 4 H)3.34-3.44 (m, 7 H) 3.54-3.63 (m, 1 H) 6.83 (dd, J=9.09, 2.53 Hz, 1 H)6.93 (dd, J=14.27, 2.40 Hz, 1 H) 6.97 (d, J=2.02 Hz, 1 H) 7.55-7.62 (m,2 H) 10.44 (s, 1 H); [M+H] calc'd for C₂₂H₂₃FN₆O, 407; found, 407.melting point 251-255° C.

Compound 22:(S)-3-fluoro-5-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)picolinonitrile

Compound 22 was prepared using a procedure analogous to that describedin connection with compound 16, except that 3,5-difluoropicolinonitrilewas used instead of 3-chloro-4-fluorobenzonitrile. ¹H NMR (400 MHz,DMSO-d6) δ (ppm): 1.83-2.02 (m, 3 H) 2.10-2.24 (m, 1 H) 2.35-2.47 (m, 4H) 3.34-3.51 (m, 7 H) 3.52-3.65 (m, 1 H) 3.94-4.03 (m, 1 H) 6.97 (d,J=1.77 Hz, 1 H) 7.38 (dd, J=13.52, 2.15 Hz, 1 H) 7.61 (d, J=1.52 Hz, 1H) 8.29 (s, 1 H) 10.45 (s, 1 H); [M+H] calc'd for C₂₁H₂₂FN₇O, 408;found, 408.

Compound 23:(S)-3-((4-phenylpiperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

1-Phenylpiperazine hydrochloride (11.9 mg, 0.060 mmol),(cyanomethyl)trimethylphosphonium iodide (0.025 g, 0.102 mmoles), and(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(0.014 g, 0.063 mmoles) were diluted with propionitrile (0.5 ml) andtreated with DIPEA (0.017 ml, 0.100 mmol). The reaction mixture wasstirred at 90° C. overnight. The reaction mixture was washed with water(1 mL) and concentrated. The residue was dissolved in DMSO (1 mL) andpurified using HPLC (acetonitrile-water, NH₄HCO₃ buffered). Thefractions were concentrated in vacuo, dissolved in dioxane-water (1:1, 2mL) and lyophilized to yield the title compound as a white solid (5.1mg, 23%). [M+H] calc'd for C₂₁H₂₅N₅O 364; found, 364.

Compound 24:(S)-3-((4-(4-fluorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 24 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₁H₂₄FN₅O 382; found,382.

Compound 25:(S)-3-((4-(4-acetylphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 25 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₃H₂₇N₅O₂ 406; found,406.

Compound 26:(S)-3-((4-(pyridin-2-yl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 26 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₀H₂₄N₆O 365; found,365.

Compound 27:(S)-3-((benzylmethyl)amino)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 27 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₁₉H₂₂N₄O 323; found,323.

Compound 28:(S)-3-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 28 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₂H₂₇N₅O₂ 394; found,394.

Compound 29:(S)-3-((4-m-tolylpiperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 29 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₂H₂₇N₅O 378; found,378.

Compound 30:(S)-3-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 30 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₂H₂₇N₅O₂ 394; found,394.

Compound 31:(S)-3-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 31 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₂H₂₇N₅O₂ 394; found,394.

Compound 32:(S)-3-((4-p-tolylpiperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 32 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₂H₂₇N₅O 378; found,378.

Compound 33:(S)-3-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 33 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₁₉H₂₃N₇O 366; found,366.

Compound 34:(S)-3-((4-(3-hydroxyphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 34 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₁H₂₅N₅O₂ 380; found,380.

Compound 35:(S)-3-((4-(4-hydroxyphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 35 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₁H₂₅N₅O₂ 380; found,380.

Compound 36:(S)-3-((4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 36 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₁H₂₃F₃N₆O 433; found,433.

Compound 37:(S)-3-((4-(4-bromophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 37 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₁H₂₄BrN₅O 444; found,444.

Compound 38:(S)-3-((4-(3-fluorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 38 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₁H₂₄FN₅O 382; found,382.

Compound 39:(S)-3-((4-(1H-benzo[d]imidazol-2-yl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 39 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₂H₂₅N₇O 404; found,404.

Compound 40:(S)-3-((4-(4-iodophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 40 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₁H₂₄IN₅O 490; found,490.

Compound 41:(S)-3-((4-(benzo[d]oxazol-2-yl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 41 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₂H₂₄N₆O₂ 405; found,405.

Compound 42:(S)-3-((4-(5-chloropyridin-2-yl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 42 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₀H₂₃ClN₆O 399; found,399.

Compound 43:(S)-3-(((4-methoxybenzyl)(methyl)amino)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 43 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₀H₂₄N₄O₂ 353; found,353.

Compound 44:(S)-3-((4-(1,3,5-triazin-2-yl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 44 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₁₈H₂₂N₈O 367; found,367.

Compound 45: (S)-methyl4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate

Compound 45 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₃H₂₇N₅O₃ 422; found,422.

Compound 46:(S)-3-((4-(3,5-difluorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 46 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₁H₂₃F₂N₅O 400; found,400.

Compound 47:(S)-3-((4-(4-chloro-3-fluorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 47 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₁H₂₃ClFN₅O 416;found, 416.

Compound 48:(S)-3-((4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 48 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₂H₂₄F₃N₅O 432; found,432.

Compound 49:(R)-3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 49 was prepared using a procedure analogous to that describedin connection with compound 2, except that(R)-methylpyrrolidine-2-carboxylate was used instead of(S)-methylpyrrolidine-2-carboxylate. ¹H NMR (DMSO-d₆) δ (ppm): 10.43 (s,1H), 7.62 (d, J=1.8 Hz, 1H), 7.40-7.48 (m, 2H), 7.29-7.40 (m, 2H), 6.99(d, J=1.8 Hz, 1H), 6.18 (br. s., 1H), 3.91-4.06 (m, 1H), 3.52-3.67 (m,1H), 3.40-3.49 (m, 3H), 3.01 (d, J=2.3 Hz, 2H), 2.56-2.65 (m, 2H), 2.43(br. s., 2H), 2.10-2.24 (m, 1H), 1.77-2.01 (m, 3H); [M+H] calc'd forC₂₂H₂₃ClN₄O, 395; found, 395.

Compound 50:(R)-3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 50 was prepared using a procedure analogous to that describedin connection with compound 1, except that(R)-methylpyrrolidine-2-carboxylate was used instead of(S)-methylpyrrolidine-2-carboxylate. ¹H NMR (DMSO-d₆) δ (ppm): 10.43 (s,1H), 7.61 (d, J=1.5 Hz, 1H), 7.21 (d, J=8.8 Hz, 2H), 6.98 (d, J=1.8 Hz,1H), 6.92 (d, J=9.1 Hz, 2H), 3.89-4.05 (m, 1H), 3.52-3.66 (m, 1H),3.37-3.48 (m, 3H), 3.10 (br. s., 4H), 2.46 (d, J=4.5 Hz, 4H), 2.07-2.25(m, 1H), 1.78-2.04 (m, 3H); [M+H] calc'd for C₂₁H₂₄ClN₅O, 398; found,398.

Compound 51:(R)-3-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 51 was prepared using a procedure analogous to that describedin connection with compound 3, except that(R)-methylpyrrolidine-2-carboxylate was used instead of(S)-methylpyrrolidine-2-carboxylate. ¹H NMR (DMSO-d₆) δ (ppm): 10.42 (s,1H), 7.60 (d, J=1.8 Hz, 1H), 7.29-7.37 (m, 2H), 7.19-7.29 (m, 2H), 6.97(d, J=1.8 Hz, 1H), 3.90-4.05 (m, 1H), 3.51-3.65 (m, 1H), 3.35-3.45 (m,1H), 2.88 (d, J=10.9 Hz, 2H), 2.08-2.25 (m, 1H), 1.82-2.05 (m, 5H),1.64-1.78 (m, 2H), 1.48-1.64 (m, 2H); [M+H] calc'd for C₂₂H₂₅ClN₄O, 397;found, 397.

Compound 52:(S)-7-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-3,4-dimethyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 52 was prepared using a procedure analogous to that describedin connection with compound 2, except that (S)-methyl2-(methylamino)propanoate was used instead of(S)-methylpyrrolidine-2-carboxylate. ¹H NMR (CHLOROFORM-d) δ (ppm): 7.80(d, J=1.8 Hz, 1H), 7.60 (br. s., 1H), 7.28-7.33 (m, 4H), 6.96-7.06 (m,1H), 6.01-6.08 (m, 1H), 4.13 (q, J=6.6 Hz, 1H), 3.47-3.58 (m, J=3.3 Hz,2H), 3.18 (d, J=2.3 Hz, 2H), 3.08 (s, 3H), 2.69-2.79 (m, 2H), 2.55 (br.s., 2H), 1.36 (d, J=7.1 Hz, 3H); [M+H] calc'd for C₂₁H₂₃ClN₄O, 383;found, 383.

Compound 53:(S)-7-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-3,4-dimethyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 53 was prepared using a procedure analogous to that describedin connection with compound 3, except that (S)-methyl2-(methylamino)propanoate was used instead of(S)-methylpyrrolidine-2-carboxylate. ¹H NMR(CHLOROFORM-d) δ (ppm):7.82-7.94 (m, 1H), 7.78 (d, J=1.8 Hz, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.15(d, J=8.3 Hz, 2H), 7.00 (br. s., 1H), 4.13 (q, J=7.0 Hz, 1H), 3.48 (br.s., 2H), 3.08 (s, 5H), 2.51 (br. s., 1H), 2.14 (d, J=2.0 Hz, 2H), 1.81(br. s., 4H), 1.37 (d, J=6.8 Hz, 3H); [M+H] calc'd for C₂₁H₂₅ClN₄O, 385.found, 385.

Compound 54:(S)-3,4-dimethyl-7-((4-phenylpiperidin-1-yl)methyl)-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 54 was prepared using a procedure analogous to that describedin connection with compound 1, except that (S)-methyl2-(methylamino)propanoate was used instead of(S)-methylpyrrolidine-2-carboxylate and 4-phenylpiperidine was usedinstead of 1-(4-chlorophenyl)piperazine. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 1.23 (d, J=6.82 Hz, 3 H) 1.82 (m, J=13.89 Hz, 2 H) 2.00 (d,J=12.88 Hz, 2 H) 2.74-2.85 (m, 1 H) 2.94-3.11 (m, 5 H) 3.47 (t, J=13.77Hz, 2 H) 4.22 (d, J=5.05 Hz, 2 H) 7.06 (d, J=2.27 Hz, 1 H) 7.18-7.26 (m,3 H) 7.29-7.36 (m, 2 H) 7.85 (d, J=2.02 Hz, 1 H) 9.30 (br. s., 1 H)10.83 (s, 1 H); [M+H] calc'd for C₂₁H₂₆N₄O, 351; found, 351.

Compound 55:(S)-3,4-dimethyl-7-((3-oxo-4-phenylpiperazin-1-yl)methyl)-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 55 was prepared using a procedure analogous to that describedin connection with compound 1, except that (S)-methyl2-(methylamino)propanoate was used instead of(S)-methylpyrrolidine-2-carboxylate and 1-phenylpiperazin-2-one was usedinstead of 1-(4-chlorophenyl)piperazine. ¹H NMR (CHLOROFORM-d) δ (ppm):7.81 (d, J=1.8 Hz, 1H), 7.68 (s, 1H), 7.37-7.45 (m, 2H), 7.29 (d, J=8.1Hz, 3H), 6.93 (d, J=1.8 Hz, 1H), 4.14 (q, J=6.8 Hz, 1H), 3.70 (t, J=5.3Hz, 2H), 3.51 (s, 2H), 3.26-3.38 (m, 2H), 3.08 (s, 3H), 2.83 (t, J=5.4Hz, 2H), 1.38 (d, J=6.8 Hz, 3H); [M+H] calc'd for C₂₀H₂₃N₅O₂, 366;found, 366.

Compound 56:(S)-7-((4-(4-fluorophenyl)-5,6-dihydropyridin-2(1H)-yl)methyl)-3,4-dimethyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 56 was prepared using a procedure analogous to that describedin connection with compound 1, except that (S)-methyl2-(methylamino)propanoate was used instead of(S)-methylpyrrolidine-2-carboxylate and4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine was used instead of1-(4-chlorophenyl)piperazine. ¹H NMR (CHLOROFORM-d) δ (ppm): 8.26 (s,1H), 7.80 (d, J=2.0 Hz, 1H), 7.29-7.38 (m, 2H), 6.93-7.05 (m, 3H),5.95-6.03 (m, 1H), 4.08-4.17 (m, 1H), 3.46-3.55 (m, 2H), 3.14 (d, J=2.8Hz, 2H), 3.07 (s, 3H), 2.66-2.75 (m, 2H), 2.48-2.57 (m, 2H), 1.35 (d,J=6.8 Hz, 3H); [M+H] calc'd for C₂₁H₂₃FN₄O, 367; found, 367.

Compound 57:(S)-3,4-dimethyl-7-((4-phenyl-5,6-dihydropyridin-1(2H)-yl)methyl)-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 57 was prepared using a procedure analogous to that describedin connection with compound 1, except that (S)-methyl2-(methylamino)propanoate was used instead of(S)-methylpyrrolidine-2-carboxylate and4-phenyl-1,2,3,6-tetrahydropyridine was used instead of1-(4-chlorophenyl)piperazine. ¹H NMR (DMSO-d₆) δ (ppm): 10.49 (s, 1H),7.68 (d, J=1.5 Hz, 1H), 7.41 (d, J=7.3 Hz, 2H), 7.32 (t, J=7.6 Hz, 2H),7.17-7.27 (m, 1H), 7.00 (d, J=1.8 Hz, 1H), 6.13 (br. s., 1H), 4.05 (q,J=6.8 Hz, 1H), 3.43 (q, J=12.9 Hz, 2H), 3.02 (d, J=2.5 Hz, 2H), 2.94 (s,3H), 2.57-2.65 (m, 2H), 2.47 (br. s., 2H), 1.17 (d, J=6.8 Hz, 3H); [M+H]calc'd for C₂₁H₂₄N₄O, 349; found, 349.

Compound 58:(S)-7-((4-(3-chlorophenyl)piperazin-1-yl)methyl)-3,4-dimethyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 58 was prepared using a procedure analogous to that describedin connection with compound 1, except that (S)-methyl2-(methylamino)propanoate was used instead of(S)-methylpyrrolidine-2-carboxylate and 1-(3-chlorophenyl)piperazine wasused instead of 1-(4-chlorophenyl)piperazine. ¹H NMR (CHLOROFORM-d) δ(ppm): 7.79 (d, J=1.5 Hz, 1H), 7.68 (br. s., 1H), 7.17 (t, J=8.1 Hz,1H), 6.89-7.06 (m, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H),6.78 (dd, J=8.3, 2.0 Hz, 1H), 4.13 (q, J=6.8 Hz, 1H), 3.45 (br. s., 2H),3.21 (br. s., 4H), 3.08 (s, 3H), 2.60 (br. s., 4H), 1.37 (d, J=6.8 Hz,3H); [M+H] calc'd for C₂₀H₂₄ClN₅O, 386; found, 386.

Compound 59:(S)-7-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-3,4-dimethyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 59 was prepared using a procedure analogous to that describedin connection with compound 1, except that (S)-methyl2-(methylamino)propanoate was used instead of(S)-methylpyrrolidine-2-carboxylate and 1-(4-chlorophenyl)piperazine wasused instead of 1-(4-chlorophenyl)piperazine. ¹H NMR (CHLOROFORM-d) δ(ppm): 7.79 (d, J=1.8 Hz, 1H), 7.72-7.78 (m, 1H), 7.17-7.24 (m, 2H),6.89-7.02 (m, 1H), 6.79-6.88 (m, 2H), 4.13 (q, J=7.0 Hz, 1H), 3.45 (br.s., 2H), 3.17 (br. s., 4H), 3.08 (s, 3H), 2.60 (br. s., 4H), 1.37 (d,J=6.8 Hz, 3H); [M+H] calc'd for C₂₀H₂₄ClN₅O, 386; found, 386.

Compound 60:(S)-7-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-4-isopropyl-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 60A: (S)-methyl6-((1-ethoxy-1-oxopropan-2-yl)(isopropyl)amino)-5-nitronicotinate:(S)-ethyl 2-(isopropylamino)propanoate (2.83 g, 17.8 mmol) was added tomethyl 6-chloro-5-nitronicotinate (1.72 g, 7.94 mmol) and the reactionmixture was stirred in a closed vial at 90° C. for 20 h. It was cooledand diluted with EtOAc (25 mL). The resulting precipitate was filteredoff, the filtrate was concentrated in vacuo and purified using flashcolumn chromatography on silica gel (220 g SiO2, hexanes:ethyl acetate4:1) to afford the title compound as yellow oil (1.12 g, 42%). ¹H NMR(400 MHz, CHLOROFORM-d) δ (ppm): 1.18 (t, J=7.07 Hz, 3 H) 1.30 (d,J=6.32 Hz, 3 H) 1.36 (d, J=6.57 Hz, 3 H) 1.66 (d, J=6.82 Hz, 3 H)3.48-3.62 (m, 1 H) 3.90 (s, 3 H) 4.03 (q, J=6.65 Hz, 1 H) 4.06-4.21 (m,2 H) 8.54 (d, J=2.02 Hz, 1 H) 8.70 (d, J=2.02 Hz, 1 H); [M+H] calc'd forC₁₅H₂₁N₃O₆, 340; found, 340.

Compound 60B: (S)-methyl4-isopropyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-b]pyrazine-7-carboxylate:(S)-methyl6-((1-ethoxy-1-oxopropan-2-yl)(isopropyl)amino)-5-nitronicotinate (0.900g, 2.65 mmol) was dissolved in dichloromethane (10 mL). To this solutionwas added triphenyl phosphite (3.0 mg, 9.7 umol), ammonium metavanadate(30 mg, 0.265 mmol) and Pt/C (5% wt., 0.120 g). The reaction mixture washydrogenated at 80 psi at 25° C. for 6 h. The mixture was filteredthrough a small pad of celite and the pad was washed withdichloromethane (20 mL). The combined filtrates were concentrated invacuo and crystallized with ethyl ether to afford the title compounds asa white solid (0.658 g, 94%). ¹H NMR (400 MHz, CHLOROFORM-d) δ (ppm):1.33 (d, J=6.82 Hz, 3 H) 1.36-1.41 (m, 6 H) 3.90 (s, 3 H) 4.34 (q,J=6.65 Hz, 1 H) 4.86 (m, 1 H) 7.52 (d, J=1.77 Hz, 1 H) 8.59 (d, J=1.77Hz, 1 H) 8.73 (br. s., 1 H); [M+H] calc'd for C₁₃H₁₇N₃O₃, 264; found,264.

Compound 60C:(S)-7-(hydroxymethyl)-4-isopropyl-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one:(S)-methyl4-isopropyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,2-b]pyrazine-7-carboxylate(0.649 g, 2.46 mmol) was dissolved in THF (8 mL) and cooled to 0° C.under nitrogen atmosphere. Sodium hydride (60% susp. in mineral oil,0.112 g, 2.80 mmol) was added in one portion. The reaction mixture wasallowed to warm to room temperature and stirred for 30 min. It was thencooled to −50° C. and LiAlH₄ (1M in THF, 9.80 mL, 9.80 mmol) was addeddropwise over 10 min. The reaction mixture was kept at −30-(−20)° C. for1 h, cooled to below −50° C. and slowly quenched with MeOH (5 mL). Theresulting solution was warmed to room temperature and subjected topreparative HPLC (1-30% acetonitrile in water, TFA buffered) to affordthe title compound as a grey solid (TFA salt, 450 mg, 52%). [M+H] calc'dfor C₁₂H₁₇N₃O₂, 236; found, 236.

Compound 60:(S)-7-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-4-isopropyl-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one:Compound 60 was prepared using a procedure analogous to that describedin connection with compound 1D, except that(S)-7-(hydroxymethyl)-4-isopropyl-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-onewas used instead of(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-oneand 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine was used instead of1-(4-chlorophenyl)piperazine. ¹H NMR (CHLOROFORM-d) δ (ppm): 8.33 (s,1H), 7.84 (d, J=1.8 Hz, 1H), 7.21-7.36 (m, 4H), 7.04 (d, J=1.5 Hz, 1H),6.06 (br. s., 1H), 4.64-4.84 (m, 1H), 4.28 (q, J=6.7 Hz, 1H), 3.52 (s,2H), 3.05-3.27 (m, 2H), 2.65-2.79 (m, 2H), 2.54 (br. s., 2H), 1.37 (d,J=6.8 Hz, 3H), 1.25-1.33 (m, 6H); [M+H] calc'd for C₂₃H₂₇ClN₄O, 411;found, 411.

Compound 61:(S)-7-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-4-isopropyl-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 61 was prepared using a procedure analogous to that describedin connection with compound 60, except that 1-(4-chlorophenyl)piperazinewas used instead of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine. ¹HNMR (CHLOROFORM-d) δ (ppm): 8.58 (s, 1H), 7.83 (d, J=2.0 Hz, 1H),7.17-7.23 (m, 2H), 7.00 (d, J=2.0 Hz, 1H), 6.80-6.86 (m, 2H), 4.67-4.81(m, 1H), 4.28 (q, J=6.7 Hz, 1H), 3.45 (s, 2H), 3.12-3.21 (m, 4H),2.54-2.66 (m, 4H), 1.37 (d, J=6.8 Hz, 3H), 1.32 (d, J=6.8 Hz, 3H), 1.29(d, J=7.1 Hz, 3H); [M+H] calc'd for C₂₂H₂₈ClN₅O, 414; found, 414.

Compound 62:(S)-7-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-4-isopropyl-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 62 was prepared using a procedure analogous to that describedin connection with compound 60, except that 4-(4-chlorophenyl)piperidinewas used instead of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine. ¹HNMR (CHLOROFORM-d) δ (ppm): 8.15 (s, 1H), 7.82 (d, J=2.0 Hz, 1H),7.22-7.30 (m, 2H), 7.13-7.19 (m, 2H), 7.00 (s, 1H), 4.66-4.82 (m, 1H),4.28 (q, J=6.8 Hz, 1H), 3.43 (s, 2H), 3.01 (br. s., 2H), 2.41-2.56 (m,1H), 2.08 (t, J=11.4 Hz, 2H), 1.57-1.87 (m, 4H), 1.36 (d, J=6.8 Hz, 3H),1.31 (d, J=6.8 Hz, 3H), 1.29 (d, J=6.8 Hz, 3H); [M+H] calc'd forC₂₃H₂₉ClN₄O, 413; found, 413.

Compound 63:(S)-7-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-4-ethyl-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one

Compound 63A: (S)-methyl 2-(tert-butoxycarbonyl(ethyl)amino)propanoate:(S)-methyl 2-(tert-butoxycarbonylamino)propanoate (10.0 g, 49.2 mmol)was dissolved in THF (100 mL) and cooled to 0° C. under nitrogen. Sodiumhydride (60% susp. in mineral oil, 3.00 g, 75.1 mmol) was added inportions over 2 min. The reaction mixture was stirred for 5 min at 0° C.and EtI (4.80 mL, 59.5 mmol) was added. It was allowed to warm to roomtemperature over the period of 1 h, stirred at room temperatureovernight and at 70° C. for 7 d. The reaction mixture was cooled,filtered and concentrated in vacuo. The solid was triturated withhexanes (2×70 mL), the triturates were concentrated in vacuo and theresidue was purified using flash column chromatography on silica gel(330 g SiO2, hexanes:ethyl acetate 19:1-9:1) to afford the titlecompounds as an oil (4.40 g, 39%). [M+H] calc'd for C₁₁H₂₁NO₄, 232;found, 232.

Compound 63B: (S)-methyl 2-(ethylamino)propanoate: (S)-methyl2-(tert-butoxycarbonyl(ethyl)amino)propanoate (4.40 g, 19.0 mmol) wasdissolved in dichloromethane and treated with TFA (10 mL). The reactionmixture was stirred for 2 h at room temperature and concentrated invacuo. The residue was diluted with brine and NaOH (aq. 50%) was addeddropwise until pH=12.5. This was extracted with EtOAc (3×30 mL). Thecombined organic extracts were dried (MgSO4), filtered and concentratedin vacuo to afford the title compound as an opaque liquid (1.85 g, 74%).[M+H] calc'd for C₆H₁₃NO₂, 132; found, 132.

Compound 63C: (S)-methyl6-((1-ethoxy-1-oxopropan-2-yl)(ethyl)amino)-5-nitronicotinate:(S)-methyl 2-(ethylamino)propanoate (1.83 g, 14.0 mmol) was added tomethyl 6-chloro-5-nitronicotinate (1.30 g, 6.00 mmol) and the reactionmixture was stirred in a closed vial at 90° C. for 1 h. It was cooledand diluted with EtOAc (25 mL). The resulting precipitate was filteredoff, the filtrate was concentrated in vacuo and purified using flashcolumn chromatography on silica gel (220 g SiO2, ethyl acetate inhexanes 0-50%) to afford the title compound as a yellow oil (1.23 g,66%). [M+H] calc'd for C₁₄H₁₉N₃O₆, 326; found, 326.

Compound 63D: (S)-methyl4-ethyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate:(S)-methyl 6-((1-ethoxy-1-oxopropan-2-yl)(ethyl)amino)-5-nitronicotinate(1.22 g, 3.92 mmol) was dissolved in dichloromethane (12 mL). To thissolution were added triphenyl phosphite (5.0 mg, 16 umol), ammoniummetavanadate (50.0 mg, 0.427 mmol) and Pt/C (5% wt., 0.200 g). Thereaction mixture was hydrogenated at 100 psi at 25° C. for 18 h. Themixture was filtered through a small pad of celite and the pad waswashed with dichloromethane (20 mL). The combined filtrates wereconcentrated in vacuo and crystallized with ethyl ether (50 mL) toafford the title compound as a white solid (0.560 g, 57%). [M+H] calc'dfor C₁₂H₁₅N₃O₃, 250; found, 250.

Compound 63E:(S)-4-ethyl-7-(hydroxymethyl)-3-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one:(S)-methyl4-ethyl-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate(0.560 g, 2.25 mmol) was dissolved in THF (5 mL) and cooled to 0° C.under nitrogen atmosphere. Sodium hydride (60% susp. in mineral oil,0.135 g, 3.38 mmol) was added in one portion. The reaction mixture wasallowed to warm to room temperature and stirred for 30 min. It was thencooled to −50° C. and LiAlH₄ (2M in THF, 3.40 mL, 6.80 mmol) was addeddropwise over 10 min. The reaction mixture was kept at −30-(−20)° C. for1 h, cooled to below −50° C. and slowly quenched with MeOH (5 mL). Theresulting solution was warmed to room temperature and subjected topreparative HPLC (1-30% acetonitrile in water, TFA buffered) to affordthe title compound as a dark oil (TFA salt, 0.587 mg, 78%). [M+H] calc'dfor C₁₁H₁₅N₃O₂, 222; found, 222.

Compound 63:(S)-7-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-4-ethyl-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-one:Compound 63 was prepared using a procedure analogous to that describedin connection with compound 1D, except that(S)-4-ethyl-7-(hydroxymethyl)-3-methyl-3,4-dihydropyrido[3,2-b]pyrazin-2(1H)-onewas used instead of(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-oneand 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine was used instead of1-(4-chlorophenyl)piperazine. ¹H NMR (CHLOROFORM-d) δ (ppm): 7.79 (d,J=1.5 Hz, 1H), 7.68 (br. s., 1H), 7.27-7.34 (m, 4H), 7.02 (s, 1H), 6.06(br. s., 1H), 4.21 (q, J=6.8 Hz, 1H), 3.98-4.12 (m, 1H), 3.44-3.61 (m,2H), 3.07-3.26 (m, 3H), 2.75 (t, J=5.2 Hz, 2H), 2.55 (br. s., 2H), 1.36(d, J=6.8 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H); [M+H] calc'd for C₂₂H₂₅ClN₄O,397; found, 397.

Compounds 64a and 64b:3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)imidazo[1,2-a]pyrido[3,2-e]pyrazin-6(5H)-oneand3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one

Compound 64A: Methyl 5-amino-6-(1H-imidazol-1-yl)nicotinate: Methyl6-chloro-5-nitronicotinate (2.17 g, 10.0 mmol) was dissolved in ethylacetate (55 mL) and imidazole (4.09 g, 60 mmol) was added. The reactionmixture was stirred at room temperature for 2 h and treated withSnCl₂-2H₂O (13.5 g, 60.0 mmol). It was heated to 70° C. for 2 h, dilutedwith potassium carbonate (sat. aq.) and extracted with ethyl acetate(5×20 mL). The combined organic extracts were dried (MgSO4), filteredand concentrated in vacuo to afford the title compound as a crude yellowsolid, which was used in the next step without further purification.[M+H] calc'd for C₁₀H₁₀N₄O₂, 219; found, 219.

Compounds 64B1 and 64B2: Methyl6-oxo-5,6-dihydroimidazo[1,2-a]pyrido[3,2-e]pyrazine-3-carboxylate andMethyl6-oxo-5,6-dihydroimidazo[1,5-a]pyrido[3,2-e]pyrazine-3-carboxylate:Crude methyl 5-amino-6-(1H-imidazol-1-yl)nicotinate from the step above(max 10.0 mmol) was suspended in 1,2-dichlorobenzene 90 mL andN,N′-carbonyl diimidazole (CDI; 2.43 g, 15.0 mmol) was added. Thereaction mixture was heated in a closed vial at 170° C. for 2 h. Thereaction mixture was cooled, poured into ethyl ether:hexanes (1:1, 300mL) and the resulting solid was filtered and subjected to flash columnchromatography on silica gel (330 g SiO2, dichloromethane:methanol19:1-6:1). The solid was suspended in ethyl ether (30 mL), filtered offand dried in vacuum to afford the title compound as a yellow solid(0.467 g, 19%, ˜2:1 mixture of imidazole regioisomers). [M+H] calc'd forC₁₁H₈N₄O₃, 245; found, 245.

Compounds 64C1 and 64C2:3-(Hydroxymethyl)imidazo[1,2-a]pyrido[3,2-e]pyrazin-6(5H)-one and3-(Hydroxymethyl)imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one: Methyl6-oxo-5,6-dihydroimidazo[1,2-a]pyrido[3,2-e]pyrazine-3-carboxylate(0.410 g, 1.68 mmol) was suspended in THF (20 mL) and sodium hydride(60% susp. in mineral oil, 0.112 g, 2.80 mmol) was added in one portion.The reaction mixture was stirred at room temperature for 1 h, cooled to−50° C. and LiAlH₄ (2M in THF, 1.7 mL, 3.4 mmol) was added dropwise over2 min. The reaction mixture was kept at −30-(−10)° C. for 3 h and moreLiAlH₄ (2M in THF, 0.7 mL and 1.0 mL, 3.4 mmol combined) was added. Thereaction mixture was cooled to −60° C. and slowly quenched with MeOH,warmed to room temperature and TFA and water were added until a clearsolution resulted. The solution was subjected to preparative HPLC (1-30%acetonitrile in water, TFA buffered) to afford the title compound as agrey solid (147 mg, 40%; ˜2:1 mixture of imidazole regioisomers). [M+H]calc'd for C₁₀H₈N₄O₂, 217; found, 217.

Compounds 64a and 64b:3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)imidazo[1,2-a]pyrido[3,2-e]pyrazin-6(5H)-oneand3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one:Compound 64 was prepared as a mixture using a procedure analogous tothat described in connection with compound 1D, except that a mixture of3-(hydroxymethyl)imidazo[1,2-a]pyrido[3,2-e]pyrazin-6(5H)-one and3-(hydroxymethyl)imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one was usedinstead of(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-oneand 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine was used instead of1-(4-chlorophenyl)piperazine. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):2.51-2.53 (m, 2 H) 2.63-2.76 (m, 2 H) 3.12 (br. s., 2 H) 3.72 (br. s., 2H) 6.20-6.23 (m, 1 H) 7.37-7.40 (m, 2 H) 7.45-7.48 (m, 2 H) 7.61 (d,J=1.26 Hz, 1 H) 7.76 (d, J=2.02 Hz, 1 H) 7.91 (s, 1 H) 8.27 (d, J=1.77Hz, 1 H) 8.38 (d, J=1.26 Hz, 1 H); [M+H] calc'd for C₂₁H₁₈ClN₅O, 392;found, 392. Minor regioisomer: ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):2.50-2.53 (m, 2 H) 2.63-2.76 (m, 2 H) 3.12 (br. s., 2 H) 3.70 (br. s., 2H) 6.20-6.23 (m, 1 H) 7.37-7.40 (m, 2 H) 7.45-7.48 (m, 2 H) 7.70 (d,J=1.77 Hz, 1 H) 7.91 (d, J=0.76 Hz, 1 H) 8.21 (d, J=1.77 Hz, 1 H) 8.91(d, J=0.76 Hz, 1 H); [M+H] calc'd for C₂₁H₁₈ClN₅O, 392; found, 392.

Compound 65:3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 65A: Methyl6-(2-(methoxycarbonyl)piperidin-1-yl)-5-nitronicotinate: Methyl6-chloro-5-nitronicotinate (2.0 g, 9.23 mmol) was added to methylpiperidine-2-carboxylate (5.2 g, 36.92 mmol) while stirring at roomtemperature. The viscous yellow reaction was heated to 90° C. for one hand then allowed to cool back to room temperature. The reaction wasdiluted with dichloromethane (20 mL) and purified via columnchromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes)to yield the title compound (2.95 g, 99% yield) as a yellow oil. [M+H]calc'd for C14H17N3O6, 324; found, 324.

Compound 65B: Methyl6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazine-3-carboxylate:Methyl6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazine-3-carboxylate(2.95 g, 9.12 mmol) was dissolved in dichloromethane (20 mL). To theyellow solution was added ammonium metavanadate (20.0 mg, 0.171 mmol),triphenyl phosphite (aprox 30 ul, 0.097 mmol), and Pt/C (300 mg, 5%w/w). The reaction mixture was pressurized with hydrogen gas (110 psi)and stirred at room temperature for 16 h. The reaction was thendepressurized and diluted with dichloromethane (100 mL) which was thenrefluxed for 30 min. The hot solution was filtered through a pad ofcelite and washed with hot dichloromethane (3×20 mL). The filtrate wasconcentrated to yield the title compound (1.91 g, 80%) as a white solid.[M+H] calc'd for C, 13; H, 15; N, 3; O, 3, 262; found, 262.

Compound 65C:3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one:Methyl6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazine-3-carboxylate(500 mg, 1.91 mmol) was taken up in tetrahydrofuran (23 mL) in an inertenvironment. To the stirred suspension at room temperature was added NaH(60% dispersion in mineral oil, 114.7 mg, 2.87 mmol) and stirred 30 min.The reaction was then cooled to −45° C. and lithium aluminum hydride (2Min THF, 1.91 mL, 3.82 mmol) was added. The reaction was stirred at atemperature between −20 and −10° C. for 1 h. The reaction was thencooled back to −60° C. and MeOH (1 mL) followed by water (1 mL) wasadded. The reaction was allowed to stir at ambient temperature for 2 hand then poured into ethyl acetate (300 mL) and water (200 mL). Thebiphasic mixture was stirred vigorously and then filtered through amedium frit. The layers were separated and the aqueous phase wasextracted with ethyl acetate (3×100 mL). The organic layers werecombined, washed with brine (100 mL), dried with sodium sulfate andconcentrated to yield the title compound (429.4 mg, 96%) as a whitesolid. [M+H] calc'd for C, 12; H, 15; N, 3; O, 2, 234; found, 234.

Compound 65:3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one:3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(100 mg, 0.43 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (103 mg, 0.41 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). Tothe stirred mixture was then added4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (94.0 mg,0.41 mmol). The reaction was heated to 90° C. with stirring 2 h. Thereaction was then cooled to room temperature and diluted with water (3mL) and filtered. The solids were collected and refluxed in ethanol (5mL) for 1 h. The suspension was cooled back to room temperature andfiltered. The precipitate was filtered off and dried in vacuum to affordthe title compound (31.8 mg, 18%) as a white solid. ¹H NMR (DMSO-d₆) δ(ppm): 10.47 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.41-7.48 (m, 2H),7.33-7.40 (m, 2H), 6.98 (d, J=2.0 Hz, 1H), 6.18 (s, 1H), 4.43-4.57 (m,1H), 3.84 (d, J=11.4 Hz, 1H), 3.42 (s, 2H), 3.01 (d, J=2.8 Hz, 2H),2.55-2.66 (m, 3H), 2.44 (br. s., 2H), 1.98-2.09 (m, 1H), 1.78-1.92 (m,1H), 1.57-1.70 (m, 1H), 1.33-1.56 (m, 3H). [M+H] calc'd for C, 23; H,25; ClN, 4; O, , 409; found, 409.

Compound 66:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(100 mg, 0.43 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (103 mg, 0.41 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). Tothe stirred mixture was then added 1-(4-chlorophenyl)piperazinehydrochloride (94.0 mg, 0.41 mmol). The reaction was heated to 90° C.with stirring for 2 h. The reaction was then cooled to room temperatureand diluted with water (3 mL) and filtered. The solids were collectedand refluxed in ethanol (5 mL) for 1 h. The suspension was cooled backto room temperature and filtered. The solids were collected to affordthe title compound (69.9 mg, 39%) as a white solid. ¹H NMR (DMSO-d₆) δ(ppm): 10.47 (s, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.21 (d, J=9.1 Hz, 2H),6.97 (d, J=1.8 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.50 (d, J=12.9 Hz, 1H),3.83 (dd, J=11.2, 2.7 Hz, 1H), 3.34 (d, J=5.6 Hz, 2H), 3.01-3.17 (m,4H), 2.55-2.65 (m, 1H), 2.37-2.48 (m, 4H), 1.98-2.08 (m, 1H), 1.85 (d,J=12.4 Hz, 1H), 1.63 (d, J=12.6 Hz, 1H), 1.32-1.56 (m, 3H). [M+H] calc'dfor C, 22; H, 26; ClN, 5; O, , 412; found, 412.

Compound 67:3-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(100 mg, 0.43 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (103 mg, 0.41 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). Tothe stirred mixture was then added 4-(4-chlorophenyl)piperidinehydrochloride (95.0 mg, 0.41 mmol). The reaction was heated to 90° C.with stirring for 2 h. The reaction was cooled to room temperature andpurified via HPLC (10-80 MeCN/H₂O, TFA buffered). The fractions werecollected and lyophilized to yield the title compound (57.3 mg, 32%) asa white solid. ¹H NMR (DMSO-d₆) δ: 13.44 (br. s., 1H), 10.82 (s, 1H),9.52 (br. s., 1H), 7.84 (d, J=2.0 Hz, 1H), 7.36-7.42 (m, 2H), 7.24 (d,J=8.3 Hz, 2H), 7.06 (d, J=2.0 Hz, 1H), 4.58 (d, J=13.1 Hz, 1H), 4.21 (d,J=4.5 Hz, 2H), 3.97 (dd, J=11.6, 2.8 Hz, 1H), 3.46 (d, J=11.6 Hz, 2H),2.96-3.07 (m, 2H), 2.79-2.85 (m, 1H), 2.67 (td, J=12.8, 2.7 Hz, 1H),2.06-2.10 (m, 1H), 1.95-2.02 (m, 2H), 1.72-1.91 (m, 3H), 1.64-1.67 (m,1H), 1.33-1.58 (m, 3H). [M+H] calc'd for C, 23; H, 27; ClN, 4; O, , 411;found, 411.

Compound 68:(S)-3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 68A: (S)-methyl6-(2-(methoxycarbonyl)piperidin-1-yl)-5-nitronicotinate: Methyl6-chloro-5-nitronicotinate (2.333 g, 10.77 mmol) was added to (S)-methylpiperidine-2-carboxylate (2.93 g, 20.46 mmol) neat while stirring. Thereaction was stirred 1 h at 90° C., cooled to room temperature and takenup in ethyl acetate (10 mL). The mixture was purified by SiO₂ (330 g,20-30% EA in Hexanes) to yield 3.4 g (98%) of the title compound as ayellow oil. [M+H] calc'd for C, 14; H, 17; N, 3; O, 6, 324; found, 324.

Compound 68B: (S)-methyl6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazine-3-carboxylate:In a bomb hydroginator, (S)-methyl6-(2-(methoxycarbonyl)piperidin-1-yl)-5-nitronicotinate (1.95 g, 6.03mmol), triphenyl phosphite (0.019 ml, 0.060 mmol), ammonium vanadate(0.056 g, 0.483 mmol) and platinum (5% on carbon, 0.235 g, 0.060 mmol)were mixed in dichloromethane (Volume: 30.2 ml) to give a suspension.The bomb was sealed and pressurized to 110 psi with hydrogen gas. Thereaction was stirred at 110 psi 16 h, depressurized, diluted with DCM(100 mL) and refluxed 10 minutes. The hot mixture was filtered throughcelite and washed with DCM (50 mL). The filtrate was concentrated invacuo to yield 1.4 g (89%) of the product as a white solid and usedwithout further purification. [M+H] calc'd for C, 13; H, 15; N, 3O, 3,262; found, 262.

Compound 68C:(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one:In round-bottomed flask, (S)-methyl6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazine-3-carboxylate(860 mg, 3.29 mmol) was dissolved in Tetrahydrofuran (Volume: 41 mL) togive a clear solution. The solution was cooled to 0° C. and NaH (197 mg,4.94 mmol) was added. The reaction was allowed to stir at RT for 0.5hour. The translucent solution was then cooled to −78° C. and LAH wasadded over two minutes. The reaction temperature was maintained between−30° C. and −20° C. for 3 hours while stirring, then cooled to −78° C.Methanol (3 ml, gas evolution) and water (1 ml) were added. The reactionwas stirred at room temperature for 30 minutes. The crude product wasadded to 400 ml ethyl acetate. Water (100 ml) was added and the mixturestirred for 1 hr. The mixture was filtered through medium frit to removetan solids which were discarded. The aqueous layer was extracted withethyl acetate (1×100 mL). The organic fractions were combined, washedonce with brine and dried with sodium sulfate and concentrated to yield743 mg (97%) of the product as a white residue. [M+H] calc'd for C, 12;H, 15; N, 3; O, 2, 234; found, 234.

Compound 68:(S)-3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-on:(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(100 mg, 0.429 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (125.0 mg, 0.51 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (225 ul, 1.3 mmol). To thestirred mixture was then added4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (109 mg,0.472 mmol). The reaction was heated to 90° C. with stirring for 16 h.The reaction was then cooled to room temperature, diluted with EtOH (3ml) and water (˜300 ul), then filtered. The solids were collected andrefluxed in ethanol (5 mL) for 2 h. The suspension was cooled back toroom temperature and filtered. The precipitate was filtered off anddried in vacuum to afford the title compound (75.1 mg, 43%) as a whitesolid. ¹H NMR (DMSO-d₆) δ (ppm): 10.47 (s, 1H), 7.66 (d, J=1.8 Hz, 1H),7.40-7.48 (m, 2H), 7.34-7.40 (m, 2H), 6.98 (d, J=2.0 Hz, 1H), 6.18 (s,1H), 4.45-4.55 (m, 1H), 3.84 (d, J=11.4 Hz, 1H), 3.42 (s, 2H), 3.01 (d,J=2.8 Hz, 2H), 2.56-2.66 (m, 3H), 2.44 (br. s., 2H), 1.98-2.08 (m, 1H),1.80-1.89 (m, 1H), 1.59-1.68 (m, 1H), 1.34-1.57 (m, 3H). [M+H] calc'dfor C, 23; H, 25; ClN, 4; O, , 409; found, 409. MP: 201.6° C.

Compound 69:(S)-3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(100 mg, 0.429 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (125.0 mg, 0.51 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (225 ul, 1.3 mmol). To thestirred mixture was then added 1-(4-chlorophenyl)piperazinehydrochloride (110 mg, 0.472 mmol). The reaction was heated to 90° C.with stirring for 16 h. The reaction was then cooled to roomtemperature, diluted with EtOH (3 ml) and water (˜300 ul), thenfiltered. The solids were collected and refluxed in ethanol (5 mL) for 2h. The suspension was cooled back to room temperature and filtered. Theprecipitate was filtered off and dried in vacuum to afford the titlecompound (67.3 mg, 43%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):10.47 (s, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.21 (d, J=9.1 Hz, 2H), 6.97 (d,J=2.0 Hz, 1H), 6.88-6.95 (m, 2H), 4.45-4.55 (m, 1H), 3.83 (dd, J=11.4,2.8 Hz, 1H), 3.35 (s, 2H), 3.05-3.16 (m, 5H), 2.60 (td, J=12.6, 2.5 Hz,1H), 2.38-2.48 (m, 3H), 2.03 (d, J=12.6 Hz, 1H), 1.77-1.91 (m, 1H), 1.63(d, J=12.6 Hz, 1H), 1.33-1.56 (m, 3H). [M+H] calc'd for C, 22; H, 26;ClN, 5; O, , 412; found, 412.

Compound 70:(S)-3-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(100 mg, 0.429 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (125.0 mg, 0.51 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (225 ul, 1.3 mmol). To thestirred mixture was then added 4-(4-chlorophenyl)piperidinehydrochloride (109 mg, 0.472 mmol). The reaction was heated to 90° C.with stirring for 16 h. The crude reaction was cooled to roomtemperature and concentrated to a residue, then taken up in 3 mL DMSOand purified via HPLC (55-90% acetonitrile in water, ammoniumbicarbonate buffer). The fractions were combined and concentrated untila white solid precipitated. The precipitate was filtered off and driedin vacuum to afford the title compound (22.1 mg, 12.5%) as a whitesolid. ¹H NMR (DMSO-d₆) δ (ppm): 10.46 (s, 1H), 7.64 (d, J=2.0 Hz, 1H),7.29-7.37 (m, 2H), 7.21-7.28 (m, 2H), 6.96 (d, J=2.0 Hz, 1H), 4.42-4.58(m, 1H), 3.83 (dd, J=11.4, 2.8 Hz, 1H), 3.32 (s, 2H), 2.80-2.95 (m, 2H),2.54-2.66 (m, 1H), 1.92-2.08 (m, 3H), 1.83 (br. s., 1H), 1.66-1.77 (m,2H), 1.33-1.66 (m, 6H). [M+H] calc'd for C, 23; H, 27; ClN, 4; O, , 411;found, 411.

Compound 71:(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(86.0 mg, 0.369 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (108.0 mg, 0.442 mmol) wasadded followed by N-ethyl-N-isopropylpropan-2-amine (193 ul, 1.1 mmol).To the stirred mixture was then added 4-(piperazin-1-yl)benzonitrile (76mg, 0.406 mmol). The reaction was heated to 90° C. with stirring for 16h. The crude reaction was cooled to room temperature and concentrated toa residue, then taken up in 3 mL DMSO and purified via HPLC (55-90%acetonitrile in water, ammonium bicarbonate buffer). The fractions werecombined and concentrated until a white solid precipitated. Theprecipitate was filtered off and dried in vacuum to afford the titlecompound (29.7 mg, 20.0%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):10.48 (s, 1H), 7.65 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 6.94-7.04 (m, 3H),4.44-4.55 (m, 1H), 3.79-3.88 (m, 1H), 3.35 (br. s., 2H), 3.30 (br. s.,4H), 2.54-2.69 (m, 1H), 2.45 (br. s., 4H), 1.97-2.09 (m, 1H), 1.80-1.90(m, 1H), 1.57-1.69 (m, 1H), 1.32-1.56 (m, 3H). [M+H] calc'd for C, 23;H, 26; N, 6; O, , 403; found, 403. MP: 212.2° C.

Compound 72:(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinonitrile

(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(89.0 mg, 0.382 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (111.0 mg, 0.458 mmol) wasadded followed by N-ethyl-N-isopropylpropan-2-amine (200 ul, 1.1 mmol).To the stirred mixture was then added 6-(piperazin-1-yl)nicotinonitrile(79 mg, 0.420 mmol). The reaction was heated to 90° C. with stirring for16 h. The crude reaction was cooled to room temperature and concentratedto a residue, then taken up in 3 mL DMSO and purified via HPLC (55-90%acetonitrile in water, ammonium bicarbonate buffer). The fractions werecombined and concentrated until a white solid precipitated. Theprecipitate was filtered off and dried in vacuum to afford the titlecompound (54.2 mg, 35.2%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):10.48 (br. s., 1H), 8.46 (d, J=2.3 Hz, 1H), 7.83 (dd, J=9.1, 2.5 Hz,1H), 7.64 (d, J=2.0 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 6.90 (d, J=9.1 Hz,1H), 4.50 (d, J=12.9 Hz, 1H), 3.83 (dd, J=11.4, 2.8 Hz, 1H), 3.55-3.70(m, 4H), 3.34 (s, 2H), 2.59 (td, J=12.6, 2.4 Hz, 1H), 2.40 (t, J=4.8 Hz,4H), 2.03 (d, J=12.6 Hz, 1H), 1.84 (d, J=12.1 Hz, 1H), 1.63 (d, J=13.6Hz, 1H), 1.29-1.56 (m, 3H). [M+H] calc'd for C, 22; H, 25; N, 7; O, ,404; found, 404.

Compound 73:(S)-N-ethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 73A: (S)-ethyl4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate:(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(400 mg, 1.715 mmol) was suspended in propionitrile (4.3 mL) and(cyanomethyl)trimethylphosphonium iodide (500.0 mg, 2.06 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (898 ul, 5.1 mmol). To thestirred mixture was then added ethyl ethyl 4-(piperazin-1-yl)benzoate(402 mg, 1.715 mmol). The reaction was heated to 90° C. with stirringfor 16 h. The reaction was then cooled to room temperature, diluted withEtOH (8 ml) and water (1 mL), then filtered. The precipitate wasfiltered off and dried in vacuum to afford the title compound (508 mg,65.9%) as a brown solid. ¹H NMR (DMSO-d₆) δ (ppm): 10.48 (s, 1H), 7.77(d, J=9.1 Hz, 2H), 7.65 (d, J=2.0 Hz, 1H), 6.90-7.01 (m, 3H), 4.50 (d,J=12.9 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.84 (dd, J=11.4, 2.8 Hz, 1H),3.35 (s, 2H), 3.28 (br. s., 4H), 2.60 (td, J=12.6, 2.5 Hz, 1H),2.40-2.47 (m, 4H), 2.03 (d, J=12.9 Hz, 1H), 1.80-1.89 (m, 1H), 1.64 (d,J=12.6 Hz, 1H), 1.33-1.57 (m, 3H), 1.28 (t, J=7.1 Hz, 3H). [M+H] calc'dfor C, 25; H, 31; N, 5; O, 3, 450; found, 450.

Compound 73B:(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid: (S)-methyl4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate(152 mg, 0.349 mmol) was taken up in dioxane (2 ml) and LiOH (1N, 2 ml,2.000 mmol) was added. The reaction was stirred 16 h at roomtemperature. The reaction was concentrated in-vacuo and the residue wastaken up in water (5 mL) and acidified (4.5N HCl) to pH 4. A whiteprecipitate formed. The precipitate was filtered off and dried in vacuumto afford the title compound (122.8 mg, 83%) as a white solid. [M+H]calc'd for C, 23; H, 27; N, 5; O, 3, 422; found, 422.

Compound 73:(S)-N-ethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (122 mg, 0.29 mmol) was taken up in DMF (2.9 mL). To the mixturewas added N-ethyl-N-isopropylpropan-2-amine (152 μl, 0.87 mmol),O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (165 mg, 0.434 mmol), and ethanamine hydrochloride(26.0 mg, 0.318 mmol). The reaction was stirred at room temperatureovernight. The reaction was purified via HPLC (10-80 MeCN/H₂O, TFAbuffered). The fractions were collected and lyophilized to yield 135 mg(85%) of the product as a white solid. ¹H NMR (DMSO-d₆) δ (ppm): 10.82(s, 1H), 9.83 (br. s., 1H), 8.25 (t, J=5.6 Hz, 1H), 7.84 (d, J=2.0 Hz,1H), 7.77 (d, J=8.8 Hz, 2H), 6.94-7.12 (m, 3H), 4.59 (d, J=13.1 Hz, 1H),4.27 (br. s., 2H), 3.85-4.10 (m, 3H), 3.43 (d, J=10.4 Hz, 2H), 3.21-3.30(m, 2H), 2.95-3.19 (m, 4H), 2.61-2.72 (m, 1H), 2.05 (d, J=11.8 Hz, 1H),1.87 (d, J=12.4 Hz, 1H), 1.66 (d, J=12.1 Hz, 1H), 1.31-1.62 (m, 3H),1.09 (t, J=7.2 Hz, 3H). [M+H] calc'd for C, 23; H, 27; N, 5; O, 3, 449;found, 449. MP: 232.6° C.

Compound 73:(S)-N-ethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:To a suspension of(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(800 mg, 3.43 mmol) was added (cyanomethyl)trimethylphosphonium iodide(1000 mg, 4.12 mmol) and DIEA (1797 μl, 10.29 mmol) andN-ethyl-4-(piperazin-1-yl)benzamide (800 mg, 3.43 mmol)). The vial washeated to 90° C. for 16 hours. The crude reaction was cooled to RT andfiltered. The resulting solid were collected and suspended in EtOH (24mL), heated to reflux, then cooled to RT and filtered. The resultingmaterial was rinsed with EtOH to give a white solid.

Compound 74:(S)-N-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (50 mg, 0.119 mmol) was taken up in DMF (0.5 mL). To the mixturewas added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (34.1 mg, 0.178 mmol), 1H-benzo[d][1,2,3]triazol-1-olhydrate (27.2 mg, 0.178 mmol), 4-methylmorpholine (0.065 mL, 0.593 mmol)and methanamine hydrochloride (8.01 mg, 0.119 mmol). The reaction wasstirred at room temperature overnight. To the stirred solution was addedwater (2 mL) and the precipitate was filtered, collected, and dried invacuum to afford the title compound (23.8 mg, 46.2%) as a white solid.¹H NMR (DMSO-d₆) δ (ppm): 10.49 (s, 1H), 8.14 (q, J=4.5 Hz, 1H),7.58-7.80 (m, 3H), 6.82-7.04 (m, 3H), 4.51 (d, J=12.9 Hz, 1H), 3.84 (dd,J=11.2, 2.7 Hz, 1H), 3.30-3.51 (m, 3H), 3.23 (br. s., 4H), 2.74 (d,J=4.5 Hz, 3H), 2.61 (td, J=12.7, 2.7 Hz, 1H), 2.49 (br. s., 3H), 2.04(d, J=12.6 Hz, 1H), 1.85 (d, J=12.1 Hz, 1H), 1.64 (d, J=12.6 Hz, 1H),1.33-1.59 (m, 3H). [M+H] calc'd for C, 24; H, 30; N, 6; O, 2, 435;found, 435.

Compound 75:(S)-N-cyclopropyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (50 mg, 0.119 mmol) was taken up in DMF (0.5 mL). To the mixturewas added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (34.1 mg, 0.178 mmol), 1H-benzo[d][1,2,3]triazol-1-olhydrate (27.2 mg, 0.178 mmol), 4-methylmorpholine (0.065 mL, 0.593 mmol)and cyclopropanamine (6.77 mg, 0.119 mmol). The reaction was stirred atroom temperature overnight. To the stirred solution was added water (2mL) and the precipitate was filtered, collected, and dried in vacuum toafford the title compound (41.2 mg, 75.0%) as a white solid. ¹H NMR(DMSO-d₆) δ (ppm): 10.48 (s, 1H), 8.13 (d, J=4.0 Hz, 1H), 7.57-7.76 (m,3H), 6.80-7.02 (m, 3H), 4.50 (d, J=13.1 Hz, 1H), 3.84 (dd, J=11.4, 2.8Hz, 1H), 3.35 (br. s., 2H), 3.22 (br. s., 4H), 2.79 (td, J=7.3, 3.9 Hz,1H), 2.60 (td, J=12.6, 2.7 Hz, 1H), 2.46 (br. s., 4H), 2.03 (d, J=12.9Hz, 1H), 1.83 (br. s., 1H), 1.64 (d, J=12.9 Hz, 1H), 1.31-1.57 (m, 3H),0.61-0.69 (m, 2H), 0.48-0.56 (m, 2H). [M+H] calc'd for C, 26; H, 32; N,6; O, 2, 461; found, 461.

Compound 76:(S)-N-isopropyl-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide

Compound 76A: (S)-ethyl6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinate:(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(330 mg, 1.415 mmol) was suspended in propionitrile (3.5 mL) and(cyanomethyl)trimethylphosphonium iodide (413.0 mg, 1.70 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (741 ul, 4.2 mmol). To thestirred mixture was then added ethyl 6-(piperazin-1-yl)nicotinate (366mg, 1.56 mmol). The reaction was heated to 90° C. with stirring for 16h. The reaction was then cooled to room temperature, diluted with EtOH(8 ml) and water (1 mL), then filtered. The precipitate was filtered offand dried in vacuum to afford the title compound (567 mg, 89%) as abrown solid. ¹H NMR (DMSO-d₆) δ (ppm): 10.48 (s, 1H), 8.63 (d, J=2.0 Hz,1H), 7.93 (dd, J=9.1, 2.3 Hz, 1H), 7.65 (d, J=1.8 Hz, 1H), 6.97 (d,J=2.0 Hz, 1H), 6.85 (d, J=9.1 Hz, 1H), 4.44-4.56 (m, 1H), 4.24 (q, J=7.1Hz, 2H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.53-3.73 (m, 4H), 3.35 (s, 2H),2.60 (td, J=12.6, 2.5 Hz, 1H), 2.41 (t, J=4.8 Hz, 4H), 2.05 (br. s.,1H), 1.85 (d, J=12.4 Hz, 1H), 1.64 (d, J=12.4 Hz, 1H), 1.34-1.57 (m,3H), 1.28 (t, 3H) [M+H] calc'd for C, 24; H, 30; N, 6; O, 3, 451; found,451

Compound 76B:(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinicacid: Compound 76B was prepared using a procedure analogous to thatdescribed in connection with Compound 73B except that (S)-ethyl6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinatewas used instead of (S)-ethyl4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoateto yield the title compound as a white solid. [M+H] calc'd for C, 22; H,26; N, 6; O, 3, 423; found, 423.

Compound 76:(S)-N-isopropyl-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide:(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinicacid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixturewas added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol),O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (101 mg, 0.266 mmol), and propan-2-amine (11.5 mg,0.195 mmol). The reaction was stirred at room temperature overnight. Thereaction was purified via HPLC (10-80 MeCN/H₂O, TFA buffered). Thefractions were collected and lyophilized to yield 64.8 mg (65%) of theproduct as a white solid. ¹H NMR (DMSO-d₆) δ (ppm): 10.84 (s, 1H), 9.93(br. s., 1H), 8.64 (d, J=2.0 Hz, 1H), 8.02-8.11 (m, 2H), 7.82 (d, J=2.0Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.96 (d, J=9.1 Hz, 1H), 4.43-4.63 (m,3H), 4.25 (s, 2H), 4.07 (dd, J=14.1, 6.6 Hz, 1H), 3.93-4.02 (m, 1H),3.37-3.55 (m, 1H), 2.96-3.25 (m, 4H), 2.68 (td, J=12.9, 2.5 Hz, 1H),2.02-2.11 (m, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.33-1.72 (m, 4H), 1.14 (d,J=6.8 Hz, 6H). [M+H] calc'd for C, 25; H, 33; N, 7; O, 2, 464; found,464.

Compound 77:(S)-N-methyl-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide

(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinicacid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixturewas added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol),O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (101 mg, 0.266 mmol), and methanamine hydrochloride(13.2 mg, 0.195 mmol). The reaction was stirred at room temperatureovernight. The reaction was purified via HPLC (10-80 MeCN/H₂O, TFAbuffered). The fractions were collected and lyophilized to yield 23.8 mg(30%) of the product as a white solid. ¹H NMR (DMSO-d₆) δ (ppm): 10.48(s, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.20 (d, J=4.5 Hz, 1H), 7.92 (dd,J=9.0, 2.1 Hz, 1H), 7.65 (s, 1H), 6.98 (d, J=1.5 Hz, 1H), 6.82 (d, J=8.8Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.77-3.94 (m, 1H), 3.56 (d, J=2.3 Hz,4H), 3.34 (s, 2H), 2.74 (d, J=4.5 Hz, 3H), 2.53-2.69 (m, 1H), 2.41 (br.s., 4H), 1.99-2.08 (m, 1H), 1.84 (br. s., 1H), 1.59-1.69 (m, 1H),1.31-1.57 (m, 3H). [M+H] calc'd for C, 25; H, 33; N, 7; O, 2, 436;found, 436.

Compound 78:(S)-N-ethyl-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide

(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinicacid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixturewas added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol),O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (101 mg, 0.266 mmol), and ethanamine hydrochloride(15.9 mg, 0.195 mmol). The reaction was stirred at room temperatureovernight. The reaction was purified via HPLC (10-80 MeCN/H₂O, TFAbuffered). The fractions were collected and lyophilized to yield 27.4 mg(34%) of the title compound as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):10.84 (s, 1H), 10.03 (br. s., 1H), 8.64 (s, 1H), 8.35 (t, J=5.2 Hz, 1H),8.04 (d, J=9.1 Hz, 1H), 7.83 (s, 1H), 6.90-7.11 (m, 2H), 4.40-4.71 (m,3H), 4.26 (s, 2H), 3.98 (d, J=11.1 Hz, 1H), 2.96-3.57 (m, 8H), 2.61-2.74(m, 1H), 2.08 (d, J=11.9 Hz, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.33-1.73 (m,4H), 1.11 (t, 3H). [M+H] calc'd for C, 24; H, 31; N, 7; O, 2, 450;found, 450.

Compound 79:(S)-N-cyclopropyl-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinamide

(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinicacid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixturewas added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol),O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (101 mg, 0.266 mmol), and cyclopropanamine (11.15mg, 0.195 mmol). The reaction was stirred at room temperature overnight.The reaction was purified via HPLC (10-80 MeCN/H₂O, TFA buffered). Thefractions were collected and lyophilized to yield 41.2 mg (50%) of theproduct as a white solid. ¹H NMR (DMSO-d₆) δ (ppm): 10.81 (s, 1H), 9.85(br. s., 1H), 8.61 (d, J=2.3 Hz, 1H), 8.30 (d, J=4.0 Hz, 1H), 8.01 (dd,J=9.0, 2.4 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 6.95(d, J=8.8 Hz, 1H), 4.42-4.64 (m, 3H), 4.24 (br. s., 2H), 3.92-4.01 (m,1H), 3.42 (br. s., 2H), 2.94-3.26 (m, 4H), 2.75-2.86 (m, 1H), 2.58-2.73(m, 1H), 2.03-2.12 (m, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.66 (d, J=12.6 Hz,1H), 1.31-1.61 (m, 3H), 0.62-0.73 (m, 2H), 0.46-0.57 (m, 2H). [M+H]calc'd for C, 25; H, 31; N, 7; O, 2, 462; found, 462.

Compound 80:7-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one

Compound 80A: Methyl6-((2-methoxy-2-oxoethyl)(methyl)amino)-5-nitronicotinate: Methyl6-chloro-5-nitronicotinate (2.0 g, 9.23 mmol) was added to methyl2-(methylamino)acetate (1.9 g, 18.47 mmol) neat while stirring at roomtemperature. The viscous yellow reaction was heated to 90° C. for onehour and then allowed to cool back to room temperature. The reaction wasdiluted with dichloromethane (20 mL) and purified using flash columnchromatography (220 g SiO₂, 20-30% gradient, ethyl acetate in hexanes)to yield 2.60 g (99% yield) of the title compound as a yellow oil. [M+H]calc'd for C, 11; H, 13; N, 3; O, 6, 284; found, 284.

Compound 80B: Methyl4-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate:Methyl 6-((2-methoxy-2-oxoethyl)(methyl)amino)-5-nitronicotinate (2.7 g,9.53 mmol) was dissolved in dichloromethane (10 mL). To the yellowsolution was added ammonium metavanadate (30.0 mg, 0.256 mmol),triphenyl phosphite (aprox 30 ul, 0.097 mmol), and Pt/C (300 mg, 5%w/w). The reaction mixture was pressurized with hydrogen gas (110 psi)and stirred at room temperature for 16 h. The reaction was thendepressurized and diluted with dichloromethane (100 mL) which was thenrefluxed for 30 min. The hot solution was filtered through a pad ofcelite and washed with hot dichloromethane (3×20 mL). The filtrate wasconcentrated in vacuo to yield the title compound (1.45 g, 68%) as awhite solid. [M+H] calc'd for C, 10; H, 11; N, 3; O, 3, 222; found, 222.

Compound 80C:7-(hydroxymethyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one:Methyl4-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate(500 mg, 2.25 mmol) was taken up in tetrahydrofuran (25 mL) in an inertenvironment. To the stirred suspension at room temperature was added NaH(60% dispersion in mineral oil, 136 mg, 3.40 mmol) and stirred 30 min.The reaction was then cooled to −45° C. and lithium aluminum hydride (2Min THF, 3.3 mL, 6.6 mmol) was added. The reaction was stirred at atemperature between −20 and −10° C. for 1 h. The reaction was thencooled back to −60° C. and MeOH (1 mL) followed by water (1 mL) wasadded. The reaction was allowed to stir at ambient temperature for 2 hand then poured into ethyl acetate (300 mL) and water (200 mL). Thebiphasic mixture was stirred vigorously and then filtered through amedium frit. The layers were separated and the aqueous phase wasextracted with ethyl acetate (3×100 mL). The organic layers werecombined, washed with brine (100 mL), dried with sodium sulfate andconcentrated to yield the title compound (415 mg, 95%) as a white solid.[M+H] calc'd for C9H11N3O2, 194; found, 194.

Compound 80:7-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one:7-(hydroxymethyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one(85.0 mg, 0.44 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). Tothe stirred mixture was then added4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (103.5 mg,0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. Thereaction was then cooled to room temperature and diluted with water (3mL) and filtered. The solids were collected and refluxed in ethanol (5mL) for 1 h. The suspension was cooled back to room temperature andfiltered. The precipitate was filtered off and dried in vacuum to affordthe title compound (30.2 mg, 19%) as a white solid. ¹H NMR (DMSO-d₆) δ(ppm): 10.51 (s, 1H), 7.64 (s, 1H), 7.41-7.47 (m, 2H), 7.34-7.40 (m,2H), 6.97 (d, J=1.8 Hz, 1H), 6.18 (s, 1H), 3.93 (s, 2H), 3.41 (s, 2H),3.01 (br. s., 2H), 2.91 (s, 3H), 2.60 (br. s., 2H), 2.39-2.47 (m, J=7.3Hz, 2H). [M+H] calc'd for C, 20; H, 21; ClN, 4; O, , 369; found, 369.

Compound 81:7-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one

7-(hydroxymethyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one(85.0 mg, 0.44 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). Tothe stirred mixture was then added 1-(4-chlorophenyl)piperazinehydrochloride (104.8 mg, 0.45 mmol). The reaction was heated to 90° C.with stirring for 2 h. The reaction was then cooled to room temperatureand diluted with water (3 mL) and filtered. The solids were collectedand refluxed in ethanol (5 mL) for 1 h. The suspension was cooled backto room temperature and filtered. The precipitate was filtered off anddried in vacuum to afford the title compound (14.7 mg, 8%) as a whitesolid. ¹H NMR (DMSO-d₆) δ (ppm): 10.50 (s, 1H), 7.63 (d, J=1.8 Hz, 1H),7.21 (d, J=9.1 Hz, 2H), 6.96 (d, J=2.0 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H),3.93 (s, 2H), 3.34 (s, 2H), 3.10 (br. s., 4H), 2.91 (s, 3H), 2.46 (br.s., 4H). [M+H] calc'd for C, 19; H, 22; ClN, 5; O, 372; found, 372.

Compound 82:7-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one

7-(hydroxymethyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one(85.0 mg, 0.44 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). Tothe stirred mixture was then added 4-(4-chlorophenyl)piperidinehydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C.with stirring for 2 h. The reaction was then cooled to room temperatureand diluted with water (3 mL) and filtered. The solids were collectedand refluxed in ethanol (5 mL) for 1 h. The suspension was cooled backto room temperature and filtered. The precipitate was filtered off anddried in vacuum to afford the title compound (18.1 mg, 11%) as a whitesolid. ¹H NMR (DMSO-d₆) δ (ppm): 10.49 (s, 1H), 7.61 (d, J=2.0 Hz, 1H),7.30-7.36 (m, 2H), 7.23-7.29 (m, 2H), 6.95 (d, J=2.0 Hz, 1H), 3.92 (s,2H), 3.32 (s, 3H), 2.84-2.92 (m, 5H), 1.98 (t, J=10.7 Hz, 2H), 1.66-1.75(m, 2H), 1.50-1.64 (m, 2H). [M+H] calc'd for C, 20; H, 23; ClN, 4O, 371;found, 371.

Compound 83:4-benzyl-7-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one

Compound 83A: Methyl6-(benzyl(2-ethoxy-2-oxoethyl)amino)-5-nitronicotinate: Methyl6-chloro-5-nitronicotinate (2.0 g, 9.23 mmol) was added to methyl2-(benzylamino)acetate (6.0 g, 31.05 mmol) neat while stirring at roomtemperature. The viscous yellow reaction was heated to 90° C. for one hand then allowed to cool back to room temperature. The reaction wasdiluted with dichloromethane (20 mL) and purified via columnchromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes)to yield the title compound (3.10 g, 90% yield) as a yellow oil. [M+H]calc'd for C, 18; H, 19; N, 3O, 6, 374; found, 374.

Compound 83B: Methyl4-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate:Methyl 6-(benzyl(2-ethoxy-2-oxoethyl)amino)-5-nitronicotinate (445 mg g,1.19 mmol) was dissolved in dichloromethane (5 mL). To the yellowsolution was added ammonium metavanadate (10.0 mg, 0.085 mmol),triphenyl phosphite (aprox 10 ul, 0.032 mmol), and Pt/C (50 mg, 5% w/w).The reaction mixture was pressurized with hydrogen gas (75 psi) andstirred at room temperature for 48 h. The reaction was thendepressurized and diluted with dichloromethane (20 mL) which was thenrefluxed for 30 min. The hot solution was filtered through a pad ofcelite and washed with hot dichloromethane (3×10 mL). The filtrate wasconcentrated to yield the title compound (250 mg, 71%) as a white solid.[M+H] calc'd for C16H15N3O3, 298; found, 298.

Compound 83C:4-benzyl-7-(hydroxymethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one:Methyl4-benzyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate(600 mg, 2.02 mmol) was taken up in tetrahydrofuran (25 mL) in an inertenvironment. To the stirred suspension at room temperature was added NaH(60% dispersion in mineral oil, 121 mg, 3.03 mmo) and stirred 30 min.The reaction was then cooled to −78° C. and lithium aluminum hydride (3mL, 2M in THF) was added. The reaction was stirred at a temperaturebetween −20 and −10° C. for 2 h. The reaction was then cooled back to−78° C. and MeOH (1 mL) followed by water (1 mL) was added. The reactionwas allowed to stir at ambient temperature for 2 h and then poured intoethyl acetate (200 mL) and water (100 mL). The biphasic mixture wasstirred vigorously and then filtered through a medium frit. The layerswere separated and the aqueous phase was extracted with ethyl acetate(2×50 mL). The organic layers were combined, washed with brine (100 mL),dried with sodium sulfate and concentrated to afford the title compound(540 mg, 99%) as a white solid. [M+H] calc'd for C, 15; H, 15; N, 3; O,2, 270; found, 270.

Compound 83:4-benzyl-7-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one:4-benzyl-7-(hydroxymethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one(100 mg, 0.37 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). Tothe stirred mixture was then added4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (104.5 mg,0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. Thereaction was then cooled to room temperature and diluted with water (3mL) and filtered. The solids were collected and refluxed in ethanol (5mL) for 1 h. The suspension was cooled back to room temperature andfiltered. The precipitate was filtered off and dried in vacuum to affordthe title compound (45.3 mg, 27%) as a white solid. ¹H NMR (DMSO-d₆) δ(ppm): 10.57 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.41-7.48 (m, 2H),7.23-7.41 (m, 7H), 7.03 (d, J=2.0 Hz, 1H), 6.19 (s, 1H), 4.72 (s, 2H),3.86 (s, 2H), 3.43 (s, 2H), 3.03 (d, J=2.8 Hz, 2H), 2.58-2.65 (m, 2H),2.44 (br. s., 2H). [M+H] calc'd for C, 26; H, 25; ClN, 4; O, 445; found,445.

Compound 84:4-benzyl-7-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one

4-benzyl-7-(hydroxymethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one(100 mg, 0.37 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). Tothe stirred mixture was then added 1-(4-chlorophenyl)piperazinehydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C.with stirring for 2 h. The reaction was then cooled to room temperatureand diluted with water (3 mL) and filtered. The solids were collectedand refluxed in ethanol (5 mL) for 1 h. The suspension was cooled backto room temperature and filtered. The precipitate was filtered off anddried in vacuum to afford the title compound (66.6 mg, 40%) as a whitesolid. ¹H NMR (DMSO-d₆) δ (ppm): 10.57 (s, 1H), 7.64 (d, J=1.8 Hz, 1H),7.33 (d, J=4.5 Hz, 4H), 7.25-7.30 (m, 1H), 7.19-7.24 (m, 2H), 7.01 (d,J=1.8 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.72 (s, 2H), 3.86 (s, 2H), 3.36(s, 2H), 3.07-3.15 (m, 4H), 2.44-2.49 (m, 4H). [M+H] calc'd for C, 25;H, 26; ClN, 5; O, 448; found, 448.

Compound 85:4-benzyl-7-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one

4-benzyl-7-(hydroxymethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one(100 mg, 0.37 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). Tothe stirred mixture was then added 4-(4-chlorophenyl)piperidinehydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C.with stirring for 2 h. The reaction was then cooled to room temperatureand purified via HPLC (55-90% acetonitrile in water, ammoniumbicarbonate buffer). The fractions were combined and concentrated untila white solid precipitated. The precipitate was filtered and dried invacuum to afford the title compound (69.9 mg, 42%) as a white solid. ¹HNMR (DMSO-d₆) δ (ppm): 10.56 (s, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.30-7.37(m, 6H), 7.23-7.30 (m, 3H), 7.00 (d, J=2.0 Hz, 1H), 4.71 (s, 2H), 3.85(s, 2H), 3.33 (s, 3H), 2.89 (d, J=11.4 Hz, 2H), 1.99 (t, J=10.6 Hz, 2H),1.67-1.78 (m, 2H), 1.48-1.66 (m, 2H). [M+H] calc'd for C, 11; H, 15; Cl,2; N, 447; found, 447.

Compound 86:3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one

Compound 86A: Ethyl4-(5-(methoxycarbonyl)-3-nitropyridin-2-yl)thiomorpholine-3-carboxylate:Methyl 6-chloro-5-nitronicotinate (1.1 g, 5.10 mmol) was added to ethylthiomorpholine-3-carboxylate (2.0 g, 11.41 mmol) neat while stirring atroom temperature. The viscous yellow reaction was heated to 90° C. forone hour and then allowed to cool back to room temperature. The reactionwas diluted with dichloromethane (20 mL) and purified via columnchromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes)to yield the title compound (1.71 g, 95%) as a yellow oil. [M+H] calc'dfor C, 15; H, 18; N, 2; O, 6; S, 356. found, 356.

Compound 86B: methyl6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazine-3-carboxylate:Ethyl4-(5-(methoxycarbonyl)-3-nitropyridin-2-yl)thiomorpholine-3-carboxylate(600 mg g, 1.69 mmol) was dissolved in dichloromethane (5 mL). To theyellow solution was added ammonium metavanadate (10.0 mg, 0.085 mmol),triphenyl phosphite (aprox 10 ul, 0.032 mmol), and Pt/C (50 mg, 5% w/w).The reaction mixture was pressurized with hydrogen gas (110 psi) andstirred at room temperature for 16 h. The reaction was thendepressurized and diluted with dichloromethane (20 mL) which wasrefluxed for 30 min. The hot solution was filtered through a pad ofcelite and washed with hot dichloromethane (3×10 mL). The filtrate wasconcentrated to yield the title compound (452 mg, 96%) as a white solid.[M+H] calc'd for C, 12; H, 13; N, 3; O, 3; S, 280; found, 280.

Compound 86C:3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one:Methyl6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazine-3-carboxylate(386 mg, 1.38 mmol) was taken up in tetrahydrofuran (25 mL) in an inertenvironment. To the stirred suspension at room temperature was added NaH(60% dispersion in mineral oil, 121 mg, 3.03 mmol) and stirred 30 min.The reaction was cooled to −78° C. and lithium aluminum hydride (3 mL,2M in THF) was added. The reaction was stirred at a temperature between−20 and −10° C. for 3 h. The reaction was cooled back to −78° C. andMeOH (1 mL) followed by water (1 mL) was added. The reaction was allowedto stir at ambient temperature for 2 h and then poured into ethylacetate (200 mL) and water (100 mL). The biphasic mixture was stirredvigorously and then filtered through a medium frit. The layers wereseparated and the aqueous phase was extracted with ethyl acetate (2×50mL). The organic layers were combined, washed with brine (100 mL), driedwith sodium sulfate and concentrated to afford the title compound (497mg, 98%) as a white solid. [M+H] calc'd for C, 11; H, 13; N, 3; O, 2; S,252; found, 252.

Compound 86:3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one:3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one(100 mg, 0.36 mmol) was suspended in propionitrile (1 mL) and(cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). Tothe stirred mixture was then added4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (104.5 mg,0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. Thereaction was then cooled to room temperature and diluted with water (3mL) and filtered. The solids were collected and refluxed in ethanol (5mL) for 1 h. The suspension was cooled back to room temperature andfiltered. The solids were collected to afford the title compound (79.5mg, 19%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm): 10.66 (s, 1H), 7.70(d, J=2.0 Hz, 1H), 7.41-7.47 (m, 2H), 7.33-7.40 (m, 2H), 7.02 (d, J=2.0Hz, 1H), 6.18 (br. s., 1H), 4.88 (dt, J=13.6, 2.7 Hz, 1H), 4.27 (dd,J=10.6, 3.0 Hz, 1H), 3.43 (d, J=3.5 Hz, 2H), 2.98-3.07 (m, 3H),2.66-2.83 (m, 3H), 2.58-2.65 (m, 2H), 2.39-2.48 (m, 3H). [M+H] calc'dfor C, 22; H, 23; ClN, 4; OS, 427; found, 427.

Compound 87:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one

3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one(Compound 86C; 100 mg, 0.36 mmol) was suspended in propionitrile (1 mL)and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) wasadded followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol).To the stirred mixture was then added 1-(4-chlorophenyl)piperazinehydrochloride (104.9 mg, 0.45 mmol). The reaction was heated to 90° C.with stirring for 2 h. The reaction was then cooled to room temperatureand diluted with water (3 mL) and filtered. The solids were collectedand refluxed in ethanol (5 mL) for 1 h. The suspension was cooled backto room temperature and filtered. The solids were collected to affordthe title compound (86.1 mg, 56%) as a white solid. ¹H NMR (DMSO-d₆) δ:10.66 (s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.16-7.26 (m, 2H), 7.00 (d, J=2.0Hz, 1H), 6.86-6.96 (m, 2H), 4.88 (dt, J=13.6, 2.7 Hz, 1H), 4.26 (dd,J=10.7, 2.9 Hz, 1H), 3.34-3.42 (m, 2H), 3.07-3.16 (m, 4H), 3.02 (td,J=12.8, 2.3 Hz, 1H), 2.65-2.83 (m, 3H), 2.43-2.48 (m, 5H). [M+H] calc'dfor C, 21; H, 24; ClN, 5; OS, 430; found, 430.

Compound 88:3-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one

3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one(Compound 86C; 100 mg, 0.36 mmol) was suspended in propionitrile (1 mL)and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) wasadded followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol).To the stirred mixture was then added 4-(4-chlorophenyl)piperidinehydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C.with stirring for 2 h. The reaction was then cooled to room temperatureand diluted with water (3 mL) and filtered. The solids were collectedand refluxed in ethanol (5 mL) for 1 h. The suspension was cooled backto room temperature and filtered. The precipitate was filtered off anddried in vacuum to afford the title compound (86.1 mg, 56%) as a whitesolid. ¹H NMR (DMSO-d₆) δ (ppm): 10.44-10.83 (m, 1H), 7.68 (d, J=1.8 Hz,1H), 7.30-7.38 (m, 2H), 7.23-7.29 (m, 2H), 6.99 (d, J=2.0 Hz, 1H),4.83-4.91 (m, 1H), 4.22-4.29 (m, 1H), 3.33 (s, 3H), 2.96-3.07 (m, 1H),2.83-2.94 (m, 2H), 2.65-2.83 (m, 3H), 2.39-2.48 (m, 1H), 1.91-2.06 (m,2H), 1.66-1.78 (m, 2H), 1.49-1.66 (m, 2H) [M+H] calc'd for C, 22; H, 25;ClN, 4; OS, 429; found, 429.

Compound 89:(R)-6-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinonitrile

Compound 89A: (R)-methyl6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazine-3-carboxylate:To a suspension of (R)-thiomorpholine-3-carboxylic acid (1.009 g, 6.86mmol) in THF was added methyl 6-chloro-5-nitronicotinate (1.35 g, 6.23mmol) and potassium carbonate (2.58 g, 18.70 mmol). The suspension washeated to reflux for 3 hours. The crude orange solution was allowed tocool to RT and filtered through a pad of celite which was washed withDCM (50 mL), and transferred to a bomb hydroginator. To the solution wasadded triphenyl phosphite (0.019 ml, 0.061 mmol), platinum (0.238 g,0.061 mmol), and ammonium metavanadate. The vessel was sealed andpressurized to 140 psi with stirring for 24 h at room temperature. Thevessel was depressurized and the mixture was diluted with DCM (100 mL)and refluxed for 30 minutes. The hot mixture was filtered through celiteand concentrated to yield 887 mg (52%) of the product as a white solid.[M+H] calc'd for C, 12; H, 13; N, 3; O, 3; S, 280; found, 280.

Compound 89B:(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one:(R)-methyl6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazine-3-carboxylate(887 mg, 3.18 mmol) was taken up in tetrahydrofuran (40 mL) in an inertenvironment. To the stirred suspension at room temperature was added NaH(191 mg, 4.76 mmol, 60% dispersion in mineral oil) and stirred 30minutes. The reaction was then cooled to −45° C. and lithium aluminumhydride (4.76 mL, 2M in THF) was added. The reaction was stirred at atemperature between −20 and −10° C. for 1 hour. The reaction was thencooled back to −78° C. and methanol (5 ml) followed by water (1 ml) wasadded. The reaction was allowed to stir at ambient temperature for 2hours and then poured into ethyl acetate (400 ml) and water (100 ml).The biphasic mixture was stirred vigorously and then filtered through amedium frit. The filtrate was collected. The layers were separated andthe aqueous phase was extracted with ethyl acetate (1×100 ml). Theorganic layers were combined, washed with brine (100 ml), andconcentrated to yield 710.8 mg (89%) of the title compound as a whitesolid. [M+H] calc'd for C, 11; H, 13; N, 3; O, 2; S, 252; found, 252.

Compound 89:(R)-6-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinonitrile:(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one(80.0 mg, 0.318 mmol) was suspended in propionitrile (0.8 mL) and(cyanomethyl)trimethylphosphonium iodide (93.0 mg, 0.382 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (167 ul, 0.955 mmol). Tothe stirred mixture was then added 6-(piperazin-1-yl)nicotinonitrile(59.9 mg, 0.318 mmol). The reaction was heated to 90° C. with stirringfor 16 h. The reaction was cooled to room temperature and left to sit 48h. The precipitate was filtered off, washed with ethanol (5 mL) anddried in vacuum to afford the title compound (53.9 mg, 40.2%) as a whitesolid. ¹H NMR (CHLOROFORM-d) δ (ppm): 8.41 (d, J=1.8 Hz, 1H), 7.78 (d,J=1.8 Hz, 2H), 7.62 (dd, J=8.8, 2.3 Hz, 1H), 6.95 (br. s., 1H), 6.60 (d,J=8.8 Hz, 1H), 5.06 (dt, J=13.6, 2.8 Hz, 1H), 4.43 (dd, J=10.4, 3.3 Hz,1H), 3.70 (br. s., 4H), 3.45 (br. s., 2H), 3.15 (td, J=12.9, 2.3 Hz,1H), 3.00 (td, J=12.8, 2.8 Hz, 1H), 2.78-2.94 (m, 2H), 2.54 (br. s.,4H), 2.40 (dd, J=13.6, 1.5 Hz, 1H). [M+H] calc'd for C, 21; H, 23; N, 7;OS, 422. found, 422.

Compound 90:(R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one(80.0 mg, 0.318 mmol) was suspended in propionitrile (0.8 mL) and(cyanomethyl)trimethylphosphonium iodide (93.0 mg, 0.382 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (167 ul, 0.955 mmol). Tothe stirred mixture was then added 4-(piperazin-1-yl)benzonitrile (59.6mg, 0.318 mmol). The reaction was heated to 90° C. with stirring for 16h. The reaction was cooled to room temperature and left to sit 48 h. Theprecipitate was filtered off, washed with ethanol (5 mL) and dried invacuum to afford the title compound (36.0 mg, 26.9%) as a white solid.¹H NMR (CHLOROFORM-d) δ (ppm): 8.26 (br. s., 1H), 7.79 (d, J=1.8 Hz,1H), 7.44-7.60 (m, 2H), 6.96 (br. s., 1H), 6.76-6.91 (m, 2H), 5.05 (dt,J=13.6, 2.7 Hz, 1H), 4.43 (dd, J=10.7, 3.2 Hz, 1H), 3.27-3.63 (m, 6H),3.15 (td, J=12.8, 2.3 Hz, 1H), 3.00 (td, J=12.8, 2.7 Hz, 1H), 2.77-2.93(m, 2H), 2.59 (br. s., 4H), 2.34-2.45 (m, 1H). [M+H] calc'd for C, 22;H, 24; N, 6; OS, 421; found, 421.

Compound 91:(R)-3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one

To a suspension of(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one(70 mg, 0.279 mmol) in propiononitrile (Volume: 696 μl) was added(cyanomethyl)trimethylphosphonium iodide (81 mg, 0.334 mmol), DIEA (146μl, 0.836 mmol) and finally4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (64.1 mg,0.279 mmol). The vial was heated to 90° C. for 12 hours. Cooled to rtand concentrated to a brown residue which was treated with MeOH (5 mL).The precipitate was filtered, the solids were collected, taken up inEtOH (15 mL) and refluxed 2 hours. Let sit at RT ON. Filtered, dried invacuum and retrieved 75.6 mg (63.6%) of the title compound as a whitesolid. ¹H NMR (CHLOROFORM-d) δ (ppm): 7.80 (d, J=1.8 Hz, 1H), 7.66 (br.s., 1H), 7.30 (d, J=3.8 Hz, 5H), 7.04 (br. s., 1H), 6.02-6.09 (m, 1H),5.06 (ddd, J=13.5, 2.8, 2.7 Hz, 1H), 4.42 (dd, J=10.5, 3.2 Hz, 1H), 3.54(br. s., 2H), 3.10-3.26 (m, 3H), 3.00 (td, J=12.8, 2.7 Hz, 1H),2.85-2.92 (m, 1H), 2.75 (br. s., 2H), 2.56 (br. s., 2H), 2.35-2.44 (m,1H). [M+H] calc'd for C, 22; H, 23; ClN, 4; OS, 427; found, 427.

Compound 92:(R)-N-ethyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 92A: (R)-ethyl4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate:To a suspension of(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one(333 mg, 1.325 mmol) in propiononitrile (3313 μl) was added(cyanomethyl)trimethylphosphonium iodide (386 mg, 1.590 mmol) and DIPEA(694 μl, 3.98 mmol) and finally ethyl 4-(piperazin-1-yl)benzoate (310mg, 1.325 mmol). The vial was heated to 90° C. for 12 hours. Thereaction was then cooled to room temperature, diluted with EtOH (8 ml)and water (1 mL), then filtered. The precipitate was filtered off anddried in vacuum to afford the title compound 508 mg, 82%) as a whitesolid. [M+H] calc'd for C, 24; H, 29; N, 5; O, 3; S, 468; found, 468.

Compound 92B:(R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid: (R)-ethyl4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate(180 mg, 0.385 mmol) was taken up in dioxane (2081 μl) and LiOH (1N,2310 μl, 2.310 mmol) was added. The reaction was stirred 16 h at roomtemperature. The reaction was concentrated in-vacuo and the residue wastaken up in water (5 mL) and acidified (4.5N HCl) to pH 4. A tanprecipitate formed which was filtered and the solids were collected,dried and determined to be the product (166 mg, 98%) as a tan solid.[M+H] calc'd for C, 22; H, 25; N, 5; O, 3S, 440; found, 440.

Compound 92:(R)-N-ethyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (50 mg, 0.114 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (32.7 mg, 0.171 mmol), 1H-benzo[d][1,2,3]triazol-1-olhydrate (26.1 mg, 0.171 mmol), and DMF (Volume: 0.5 mL) were stirredtogether to give a yellow solution. Ethanamine hydrochloride (9.28 mg,0.114 mmol) and 4-methylmorpholine (0.065 mL, 0.593 mmol) were added.The reaction was stirred at room temperature for 4 hours. The crudereaction was purified via HPLC (55-90% acetonitrile in water, ammoniumbicarbonate buffer). The fractions were combined and concentrated untila white solid precipitated. The precipitate was filtered off and driedin vacuum to afford the title compound (12.0 mg, 22.6%) as a whitesolid. ¹H NMR (CHLOROFORM-d) δ (ppm): 7.79 (s, 1H), 7.68 (d, J=8.8 Hz,2H), 7.53 (s, 1H), 6.85-7.00 (m, 3H), 5.96 (br. s., 1H), 5.06 (d, J=13.4Hz, 1H), 4.43 (dd, J=10.5, 3.4 Hz, 1H), 3.39-3.54 (m, 4H), 3.30 (br. s.,4H), 3.15 (td, J=12.9, 2.3 Hz, 1H), 3.00 (br. s., 1H), 2.87 (d, J=10.4Hz, 2H), 2.60 (br. s., 4H), 2.42 (d, J=1.5 Hz, 1H), 1.25 (t, J=7.2 Hz,3H). [M+H] calc'd for C, 24; H, 30; N, 6; O, 2; S, 467; found, 467. MP:288.9° C.

Compound 93:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-6(5H)-one

Compound 93A: methyl6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazine-3-carboxylate:To a suspension of methyl morpholine-3-carboxylate (2.0 g, 13.78 mmol)in THF was added methyl methyl 6-chloro-5-nitronicotinate (2.71 g, 12.53mmol) and potassium carbonate (5.19 g, 37.6 mmol). The suspension washeated to reflux for 3 hours. The crude orange solution was allowed tocool to RT and filtered through a pad of celite which was washed withDCM (50 mL) and transferred to a bomb hydroginator. To the solution wasadded triphenyl phosphite (0.039 ml, 0.125 mmol), platinum (5%, 0.489 g,0.125 mmol), and ammonium metavanadate (0.117 g, 1.0 mmol). The vesselwas sealed and pressurized to 140 psi with stirring for 24 h at roomtemperature. The vessel was depressurized and the mixture was dilutedwith DCM (100 mL) and refluxed for 30 minutes. The hot mixture wasfiltered through celite and concentrated to yield 1.98 g (60%) of theproduct as a white solid. [M+H] calc'd for C, 12; H, 13; N, 3; O, 4,264; found, 264.

Compound 93B:3-(hydroxymethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-6(5H)-one:Methyl6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazine-3-carboxylate(1000 mg, 3.80 mmol) was taken up in tetrahydrofuran (47 mL) in an inertenvironment. To the stirred suspension at room temperature was added NaH(228 mg, 5.70 mmol, 60% dispersion in mineral oil) and stirred 30minutes. The reaction was then cooled to −45° C. and lithium aluminumhydride (11.4 mL, 1M in THF) was added. The reaction was stirred at atemperature between −20 and −10° C. for 1 hour. The reaction was thencooled back to −78° C. and methanol (3 ml) followed by water (1 ml) wasadded. The reaction was allowed to stir at ambient temperature for 2hours and then poured into ethyl acetate (400 ml) and water (100 ml).The biphasic mixture was stirred vigorously and then filtered through amedium frit. The filtrate was collected. The layers were separated andthe aqueous phase was extracted with ethyl acetate (1×100 ml). Theorganic layers were combined, washed with brine (100 ml), andconcentrated to yield 657 mg (73.5%) of the title compound as a whitesolid. [M+H] calc'd for C, 11; H, 13; N, 3; O, 3, 236; found, 236.

Compound 93:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-6(5H)-one:To a suspension of3-(hydroxymethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-6(5H)-one(73.2 mg, 0.311 mmol) in propiononitrile (778 μl) was added(cyanomethyl)trimethylphosphonium iodide (91 mg, 0.373 mmol) and DIPEA(163 μl, 0.934 mmol) and finally 1-(4-chlorophenyl)piperazine (61.2 mg,0.311 mmol). The mixture was heated to 90° C. for 4 hours. The crudeproduct was cooled to RT and left to sit 16 hours, then treated withMeOH (5 mL). The precipitate was collected and refluxed in EtOH (15 mL)2 hours. The suspension was cooled to room temperature and filtered toretrieve the title compound (75.6 mg, 58.7%) as a white solid. ¹H NMR(CHLOROFORM-d) δ (ppm): 7.82 (d, J=1.8 Hz, 1H), 7.72 (br. s., 1H),7.16-7.24 (m, 2H), 6.99 (br. s., 1H), 6.77-6.89 (m, 2H), 4.41 (dd,J=11.5, 3.7 Hz, 1H), 4.26 (dd, J=13.3, 1.6 Hz, 1H), 3.95-4.12 (m, 2H),3.59-3.75 (m, 2H), 3.46 (br. s., 2H), 3.16 (br. s., 4H), 2.94-3.06 (m,1H), 2.60 (br. s., 4H). [M+H] calc'd for C, 21; H, 24; ClN, 5; O, 2,414; found, 414.

Compound 94:7-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one

Compound 94A: Ethyl 2-(isopropylamino)acetate: To a suspension of ethyl2-aminoacetate hydrochloride (20 g, 143.28 mmol) in THF (400 mL) wasadded glacial acetic acid (20 mL) followed by acetone (11.59 mL, 151.62mmol). The reaction was stirred 30 min at room temperature. Sodiumtriacetoxyborohydride (60.73 g, 286.56 mmol) was added over the courseof one hour. The reaction was poured slowly into a vigorously stirredbiphasic mixture of water (300 mL) and ethyl acetate (800 mL). Theaqueous layer was adjusted to pH 13 using a solution of 50% (weight)NaOH. The mixture was stirred 30 min and poured into a separatoryfunnel. The organic layer was collected and the aqueous layer was backextracted with ethyl acetate (3×200 mL). The organic layers werecombined, washed with brine (300 mL), dried with sodium sulfate, andconcentrated to yield the title compound (17.6 g, 85%) as a translucentoil which was used in the next step without further purification. [M+H]calc'd for C, 7; H, 15; NO, 2, 146; found, 146.

Compound 94B: Methyl6-((2-ethoxy-2-oxoethyl)(isopropyl)amino)-5-nitronicotinate: Methyl6-chloro-5-nitronicotinate (2 g, 9.23 mmol) was added to ethyl2-(isopropylamino)acetate (5.0 g, 34.5 mmol) neat while stirring at roomtemperature. The viscous yellow reaction was heated to 90° C. for one hand then allowed to cool back to room temperature. The reaction wasdiluted with dichloromethane (20 mL) and purified via columnchromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes)to yield the title compound (2.39 g, 83%) as a yellow oil. [M+H] calc'dfor C, 14; H, 19; N, 3; O, 6, 326; found, 326.

Compound 94C: Methyl4-isopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate:Methyl 6-((2-ethoxy-2-oxoethyl)(isopropyl)amino)-5-nitronicotinate (2.39g, 7.35 mmol) was dissolved in dichloromethane (10 mL). To the yellowsolution was added ammonium metavanadate (15.0 mg, 1.13 mmol), triphenylphosphite (aprox 10 ul, 0.032 mmol), and Pt/C (240 mg, 5% w/w). Thereaction mixture was pressurized with hydrogen gas (110 psi) and stirredat room temperature for 16 h. The reaction was then depressurized anddiluted with dichloromethane (80 mL) which was then refluxed for 30 min.The hot solution was filtered through a pad of celite and washed withhot dichloromethane (3×20 mL). The filtrate was concentrated to yieldthe title compound (1.70 g, 93%) as a white solid. [M+H] calc'd for C,12; H, 15; N, 3; O, 3, 250; found, 250.

Compound 94D:7-(hydroxymethyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one:Methyl4-isopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate(1.3 g, 5.45 mmol) was suspended in tetrahydrofuran (68 mL). The whitesuspension was cooled to 0° C. and NaH (60% dispersion in mineral oil,0.327 g, 8.17 mmol) was added. The reaction was removed from the icebath and allowed to stir at RT for 0.5 h. The solution was then cooledto −78° C. and LiAlH₄ was added over two min. A temperature between −30and −20° C. was maintained. The reaction was cooled to −78° C. and MeOH(2 mL) was added. The reaction was stirred at room temperature 30 min.The reaction was poured into ethyl acetate (400 mL) and water (100 mL),and stirred for 1 hr. The mixture was filtered through medium frit toremove tan solids. The aqueous layer was extracted with ethyl acetate(1×100 mL). The organic fractions were combined, washed once with brine(100 mL), dried with sodium sulfate and concentrated to the titlecompound (1.10 g, 91%) as a white solid. [M+H] calc'd for C, 11; H, 15;N, 3; O, 2, 222; found, 222.

Compound94:-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one:7-(hydroxymethyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one(100 mg, 0.452 mmol) was taken up as a suspension in propiononitrile (1mL). Next was added (cyanomethyl)trimethylphosphonium iodide (132 mg,0.542 mmol) followed by DIPEA (0.237 mL, 1.356 mmol). To the stirredwhite suspension was then added the4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (114 mg,0.50 mmol). The reaction was heated to 90° C. and stirred overnight. Thecrude reaction was cooled to room temperature and concentrated to aresidue, then taken up in 3 mL DMSO and purified via HPLC (55-90%acetonitrile in water, ammonium bicarbonate buffer). The fractions werecombined and concentrated until a white solid precipitated. Theprecipitate was filtered off and dried in vacuum to afford the titlecompound (46.9 mg, 26%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm):10.50 (s, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.40-7.46 (m, 2H), 7.34-7.39 (m,2H), 6.98 (d, J=2.0 Hz, 1H), 6.18 (br. s., 1H), 4.76-4.87 (m, 1H), 3.81(s, 2H), 3.40 (s, 2H), 3.01 (d, J=2.8 Hz, 2H), 2.60 (t, J=5.6 Hz, 2H),2.43 (br. s., 2H), 1.12 (d, J=6.8 Hz, 6H). [M+H] calc'd for C, 22; H,25; ClN, 4; O, 397; found, 397.

Compound 95:7-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one

The7-(hydroxymethyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one(100 mg, 0.452 mmol) was weighed into a vial and taken up as asuspension in propiononitrile (1 mL). Next was added(cyanomethyl)trimethylphosphonium iodide (132 mg, 0.542 mmol) followedby DIEA (0.237 mL, 1.356 mmol). To the stirred white suspension was thenadded the 1-(4-chlorophenyl)piperazine hydrochloride (116 mg, 0.50mmol). The reaction was stirred overnight at 90° C. The crude reactionwas cooled to room temperature and concentrated to a residue, then takenup in DMSO (3 mL) and purified via HPLC (55-90% acetonitrile in water,ammonium bicarbonate buffer). The fractions were combined andconcentrated until a white solid precipitated. The precipitate wasfiltered off and dried in vacuum to afford the title compound (46.6 mg,26%) as a white solid. ¹H NMR (DMSO-d₆) δ (ppm): 10.49 (s, 1H), 7.63 (d,J=2.0 Hz, 1H), 7.21 (d, J=9.1 Hz, 2H), 6.97 (d, J=1.8 Hz, 1H), 6.92 (d,J=9.1 Hz, 2H), 4.74-4.87 (m, 1H), 3.81 (s, 2H), 3.33 (d, J=2.0 Hz, 2H),3.01-3.15 (m, 4H), 2.41-2.48 (m, 4H), 1.12 (d, J=6.8 Hz, 6H). [M+H]calc'd for C, 21; H, 26; ClN, 5; O, 400; found, 400.

Compound 96:7-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one

The7-(hydroxymethyl)-4-isopropyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one(100 mg, 0.452 mmol) suspended in propionitrile (1 mL). To this wasadded (cyanomethyl)trimethylphosphonium iodide (132 mg, 0.542 mmol)followed by DIEA (0.237 mL, 1.356 mmol) and 4-(4-chlorophenyl)piperidinehydrochloride (115 mg, 0.50 mmol). The reaction was stirred at 90° C.overnight. The crude reaction was cooled to room temperature andconcentrated to a residue, then taken up in DMSO (3 mL) and purified viaHPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). Thefractions were combined and concentrated until a white solidprecipitated. The precipitate was filtered and dried in vacuum to affordthe title compound (28.3 mg, 16%) as a white solid. ¹H NMR (DMSO-d₆) δ(ppm): 10.49 (s, 1H), 7.62 (d, J=2.0 Hz, 1H), 7.29-7.37 (m, 2H),7.18-7.29 (m, 2H), 6.96 (d, J=2.0 Hz, 1H), 4.75-4.87 (m, 1H), 3.81 (s,2H), 3.32 (d, J=12.9 Hz, 3H), 2.88 (d, J=11.1 Hz, 2H), 1.87-2.07 (m,2H), 1.65-1.77 (m, 2H), 1.57 (dd, J=12.4, 3.3 Hz, 2H), 1.10 (d, 6H).[M+H] calc'd for C, 22; H, 27; ClN, 4; O, 399; found, 399.

Compound 97:7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-2-methyl-1,3,4,10a-tetrahydro-2H,9H-2,4a,5,9-tetraaza-phenanthren-10-one

Compound 97A:10-Oxo-1,3,4,9,10,10a-hexahydro-2,4a,5,9-tetraaza-phenanthrene-2,7-dicarboxylicacid 2-tert-butyl ester 7-methyl ester: To a suspension of4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1169 mg, 5.08 mmol)in THF (46 mL) was added methyl 6-chloro-5-nitronicotinate (1000 mg,4.62 mmol) and K₂CO₃ (638 mg, 4.62 mmol). The suspension was heated toreflux for 2 hours, cooled to room temperature, and filtered through apad of celite. The celite was washed with DCM (50 mL) and the organicportions were combined. The solution was charged into a bombhydroginator, then treated with triphenyl phosphite (0.015 ml, 0.048mmol), ammonium vanadate (44 mg, 0.380 mmol), and platinum (1.853 g,0.475 mmol). The reaction was sealed and pressurized with hydrogen gas(150 psi) overnight. The reaction was then diluted with DCM (100 mL) andheated to reflux for 1 hr. The hot mixture was filtered through celite,washed with DCM (50 mL), and concentrated to 1.65 g (96%) of the titlecompound as an off-white solid. [M+H] calc'd for C, 17; H, 22; N, 4; O5,363; found, 363.

Compound 97B:7-Hydroxymethyl-10-oxo-1,3,4,9,10,10a-hexahydro-2,4a,5,9-tetraaza-phenanthrene-2-carboxylicacid tert-butyl ester:10-Oxo-1,3,4,9,10,10a-hexahydro-2,4a,5,9-tetraaza-phenanthrene-2,7-dicarboxylicacid 2-tert-butyl ester 7-methyl ester (545 mg, 1.504 mmol) was taken upin tetrahydrofuran (18 mL) in an inert environment. To the stirredsuspension at room temperature was added NaH (90 mg, 2.26 mmol, 60%dispersion in mineral oil) and stirred 30 minutes. The reaction was thencooled to −45° C. and lithium aluminum hydride (2.26 ml, 2M in THF) wasadded. The reaction was stirred at a temperature between −20 and −10° C.for 1 hour. The reaction was then cooled back to −60° C. and MeOH (5 ml)followed by water (1 ml) was added. The reaction was allowed to stir atambient temperature for 2 hours and then poured into ethyl acetate (400ml) and water (100 ml). The biphasic mixture was stirred vigorously andthen filtered through a medium frit. The filtrate was collected. Thelayers were separated and the aqueous phase was extracted with ethylacetate (1×100 ml). The organic layers were combined, washed with brine(100 ml), and concentrated to 429.4 mg (96%) of the title compound as anoff-white solid. [M+H] calc'd for C, 16; H, 22; N, 4; O, 4, 335; found,335

Compound 97C:7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-10-oxo-1,3,4,9,10,10a-hexahydro-2,4a,5,9-tetraaza-phenanthrene-2-carboxylicacid tert-butyl ester:7-Hydroxymethyl-10-oxo-1,3,4,9,10,10a-hexahydro-2,4a,5,9-tetraaza-phenanthrene-2-carboxylicacid tert-butyl ester (22.0 mg, 0.598 mmol) was suspended inpropionitrile (1.5 mL) and (cyanomethyl)trimethylphosphonium iodide(174.0 mg, 0.718 mmol) was added followed byN-ethyl-N-isopropylpropan-2-amine (313 ul, 1.794 mmol). To the stirredmixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (139mg, 0.598 mmol). The reaction was heated to 90° C. with stirring for 16h. The crude reaction was cooled to room temperature and purified onsilica column (24 g, 25% THF in ethyl acetate). The fractions werecombined and concentrated to afford 250.9 mg (82%) of the title compoundas a brown solid in 80% purity. [M+H] calc'd for C, 26; H, 33; ClN, 6;O, 3, 513; found, 513.

Compound 97D:7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-1,3,4,10a-tetrahydro-2H,9H-2,4a,5,9-tetraaza-phenanthren-10-one:7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-10-oxo-1,3,4,9,10,10a-hexahydro-2,4a,5,9-tetraaza-phenanthrene-2-carboxylicacid tert-butyl ester (250 mg, 0.487 mmol) was dissolved indichloromethane (5 mL) and trifluoroacetic acid (3 mL) was added whilestirring at room temperature. The reaction was stirred for 16 h andconcentrated to a residue. The residue was dissolved in DMF and purifiedvia HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer).The fractions were combined and concentrated until a white solidprecipitated. The precipitate was filtered off and dried in vacuum toafford the title compound (17.8 mg, 8.8%) as a white solid. ¹H NMR(DMSO-d₆) δ (ppm): 10.68 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.14-7.30 (m,2H), 7.03 (d, J=2.0 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.33 (d, J=11.4 Hz,1H), 3.97 (dd, J=11.0, 3.4 Hz, 1H), 3.45 (dd, J=12.5, 2.9 Hz, 4H),3.32-3.36 (m, 4H), 3.16 (d, J=9.6 Hz, 1H), 3.06-3.13 (m, 4H), 2.72-2.87(m, 3H). [M+H] calc'd for C, 26; H, 33; ClN, 6; O, 3, 413; found, 413.

Compound 97:7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-2-methyl-1,3,4,10a-tetrahydro-2H,9H-2,4a,5,9-tetraaza-phenanthren-10-one:To a solution of7-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-1,3,4,10a-tetrahydro-2H,9H-2,4a,5,9-tetraaza-phenanthren-10-one(139 mg, 0.337 mmol) in DMF (3.4 mL) cooled to 0° C. was added potassiumcarbonate (233 mg, 1.683 mmol) and methyl iodide (2 M in THF, 0.168 mL).The reaction was stirred 1 h at 0° C. and filtered through celite. Thefiltrate was purified via HPLC (55-90% acetonitrile in water, ammoniumbicarbonate buffer). The fractions were combined and concentrated untila white solid precipitated. The precipitate was filtered off and driedin vacuum to afford the title compound (4.6 mg, 3.2%) as a white solid.¹H NMR (DMSO-d₆) δ (ppm): 10.59 (s, 1H), 7.68 (d, J=1.8 Hz, 1H),7.15-7.28 (m, 2H), 7.01 (d, J=2.0 Hz, 1H), 6.85-6.97 (m, 2H), 4.17-4.30(m, 1H), 3.88 (dd, J=10.6, 3.3 Hz, 1H), 3.37 (s, 2H), 3.14-3.20 (m, 1H),3.06-3.14 (m, 4H), 2.84 (d, J=11.6 Hz, 1H), 2.74 (td, J=12.4, 3.0 Hz,1H), 2.44-2.48 (m, 4H), 2.26 (s, 3H), 1.91-2.02 (m, 2H). [M+H] calc'dfor C, 22; H, 27; ClN, 6; O, 427; found, 427.

Compound 98:(R)-N-methyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

In a vial equipped with a stir bar was charged(R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (50 mg, 0.114 mmol) was taken up in DMF (1.14 mL). To the mixturewas added N-ethyl-N-isopropylpropan-2-amine (59 μl, 0.34 mmol),O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (64.9 mg, 0.171 mmol), and methanamine hydrochloride(8.45 mg, 0.125 mmol). The reaction was stirred at room temperatureovernight. The reaction was purified via HPLC (55-90% acetonitrile inwater, ammonium bicarbonate buffer). The fractions were collected andlyophilized to yield 25.1 mg (49%) of the product as a white solid. ¹HNMR (CHLOROFORM-d) δ: 8.37 (br. s., 1H), 7.58-7.89 (m, 3H), 7.15 (br.s., 1H), 6.87 (d, J=8.8 Hz, 2H), 6.07 (d, J=4.5 Hz, 1H), 5.06 (dt,J=13.6, 2.5 Hz, 1H), 4.42 (dd, J=10.1, 3.8 Hz, 1H), 3.55 (br. s., 2H),3.36 (br. s., 4H), 3.08-3.24 (m, 1H), 2.56-3.08 (m, 8H), 2.40 (dd,J=13.5, 1.1 Hz, 1H), 1.74 (br. s., 2H). [M+H] calc'd for C, 23; H, 28;N, 6; O, 2; S, 453; found, 453.

Compound 99:(R)-N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

In a vial equipped with a stir bar was charged(R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (50 mg, 0.114 mmol) was taken up in DMF (1.14 mL). To the mixturewas added N-ethyl-N-isopropylpropan-2-amine (59 μl, 0.34 mmol),O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluroniumhexafluorophosphate (64.9 mg, 0.171 mmol), and cyclopropanamine (9.16uL, 0.125 mmol). The reaction was stirred at room temperature overnight.The reaction was purified via HPLC (55-90% acetonitrile in water,ammonium bicarbonate buffer). The fractions were collected andlyophilized to yield 25.1 mg (49%) of the product as a white solid ¹HNMR (CHLOROFORM-d) δ: 8.42 (br. s., 1H), 7.78 (d, J=1.5 Hz, 1H), 7.65(d, J=8.8 Hz, 2H), 7.13 (br. s., 1H), 6.85 (d, J=9.1 Hz, 2H), 6.17 (d,J=2.3 Hz, 1H), 5.05 (ddd, J=13.5, 2.7, 2.5 Hz, 1H), 4.42 (dd, J=10.4,3.5 Hz, 1H), 3.53 (br. s., 2H), 3.34 (br. s., 4H), 3.14 (td, J=12.9, 2.3Hz, 1H), 2.99 (td, J=12.8, 2.7 Hz, 1H), 2.78-2.93 (m, 3H), 2.68 (br. s.,4H), 2.39 (dd, J=13.6, 1.3 Hz, 1H), 0.80-0.90 (m, 2H), 0.54-0.67 (m,2H). [M+H] calc'd for C, 23; H, 28; N, 6; O, 2; S, 479; found, 479.

Compound 100:6-(4-((6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinonitrile

3-(hydroxymethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-6(5H)-one(70.0 mg, 0.298 mmol) was suspended in propionitrile (0.74 mL) and(cyanomethyl)trimethylphosphonium iodide (87.0 mg, 0.357 mmol) was addedfollowed by N-ethyl-N-isopropylpropan-2-amine (115 ul, 0.893 mmol). Tothe stirred mixture was then added 6-(piperazin-1-yl)nicotinonitrile(56.0 mg, 0.298 mmol). The reaction was heated to 90° C. with stirringfor 16 h. The reaction was cooled to room temperature and left to sit 48h. The precipitate was filtered off, washed with methanol (5 mL) anddried in vacuum to afford the title compound (72.5 mg, 60.1%) as a whitesolid. ¹H NMR (CHLOROFORM-d) δ: 8.41 (d, J=1.8 Hz, 1H), 8.20 (br. s.,1H), 7.80 (d, J=2.0 Hz, 1H), 7.61 (dd, J=9.0, 2.4 Hz, 1H), 6.99 (br. s.,1H), 6.59 (d, J=9.1 Hz, 1H), 4.42 (dd, J=11.5, 3.7 Hz, 1H), 4.26 (dd,J=13.3, 1.6 Hz, 1H), 3.95-4.12 (m, 2H), 3.58-3.80 (m, 6H), 3.45 (s, 2H),2.92-3.08 (m, 1H), 2.53 (br. s., 4H). [M+H] calc'd for C, 21; H, 23; N,7; O, 2, 406; found, 406.

Compound 101: (S)-ethyl4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate

Compound 101 was prepared using a procedure analogous to that describedin connection with compound 23. [M+H] calc'd for C₂₄H₂₉N₅O₃ 436; found,436.1.

Compound 102:(S)-4-(4-((6-oxo-6,6a,7,8-tetrahydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

Compound 102A: (S)-methyl6-(2-(methoxycarbonyl)azetidin-1-yl)-5-nitronicotinate: (S)-methylazetidine-2-carboxylate hydrochloride (1 g, 6.60 mmol) was diluted withTetrahydrofuran (Volume: 20 ml) and treated with TRIETHYLAMINE (0.919ml, 6.60 mmol). The reaction mixture was stirred vigorously andsonicated periodically, until a fine suspension resulted. This wasstirred for 1 h and filtered through a small plug of celite. The plugwas washed well with THF (20 mL) and the combined filtrate and washeswere treated with methyl 6-chloro-5-nitronicotinate (0.714 g, 3.30mmol). The reaction mixture was concentrated in vacuo and heated briefly(5 min) to 80° C. LCMS showed complete conversion. The reaction mixturewas diluted with DCM (10 mL) and purified using flash columnchromatography on silica gel (80 g SiO2, 20-30% ethyl acetate inhexanes) to afford the title compound (S)-methyl6-(2-(methoxycarbonyl)azetidin-1-yl)-5-nitronicotinate (0.90 g, 3.05mmol, 92% yield) as a yellow oil. [M+H] calc'd for C₁₂H₁₃N₃O₆, 295;found, 295.

Compound 102B: (S)-methyl6-oxo-6,6a,7,8-tetrahydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazine-3-carboxylate:(S)-methyl 6-(2-(methoxycarbonyl)azetidin-1-yl)-5-nitronicotinate (0.90g, 3.05 mmol) was dissolved in dichloromethane (Volume: 15.24 ml) and tothis solution was added triphenyl phosphite (9.46 mg, 0.030 mmol),ammonium metavanadate (0.021 g, 0.183 mmol) and Pt/C (5% wt.) (0.119 g,0.030 mmol). The reaction mixture was hydrogenated at 100 psi at 25° C.for 2 h. LCMS showed complete conversion of the starting material to thecorresponding amine, but no cyclization product was observed. Thereaction mixture was filtered through a short plug of celite and theplug and precipitate were washed well with dichloromethane (30 mL) andmethanol (20 mL). The combined filtrates were concentrated in vacuo (LC:CR1) and dissolved in AcOH (5 mL) (LC: AA-rt). This solution was heatedto 80° C. for 5 min (LCMS—AA-90C-5 min—complete conversion to thedesired product) and concentrated in vacuo. The residue was crystallizedwith ethyl ether (20 mL) and sonicated until a fine suspension wasobtained The precipitate was filtered off and dried in vacuum to afford(S)-methyl6-oxo-6,6a,7,8-tetrahydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazine-3-carboxylate(0.5840, 2.504 mmol, 82% yield) as a light pink solid. [M+H] calc'd forC₁₁H₁₁N₃O₃, 234; found, 234.

Compound 102C:(S)-3-(hydroxymethyl)-7,8-dihydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one:(S)-methyl6-oxo-6,6a,7,8-tetrahydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazine-3-carboxylate(0.570 g, 2.444 mmol) was suspended in Tetrahydrofuran (Volume: 8.15 ml)under nitrogen atmosphere and NaH (196 mg, 4.9 mmol) was added inseveral portions over 2 min. The reaction mixture was stirred at roomtemperature for 10 min and cooled to below −50° C. lithium aluminumhydride (2.200 ml, 4.40 mmol) was added over the period of 5 min and thereaction was kept at a temperature between −30 and −20° C. for 1 h(LCMS: >95% conversion). The mixture was cooled to below −50° C. andMeOH (4 mL) was added. Water (1 mL) was added and the reaction mixturewas stirred at rt for 10 min. Rochelle salt (20% solution) was added (10mL) and the mixture was extracted with EtOAc (3×30 mL) and THF (3×100mL). The combined organic extracts were dried (Na2SO4 and MgSO4),filtered and concentrated in vacuo. The residue was suspended inTHF/Ethyl ether (1:1, 20 mL), filtered off and dried in vacuum to afford(S)-3-(hydroxymethyl)-7,8-dihydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(0.332 g, 1.618 mmol, 66.2% yield) as a light tan solid. [M+H] calc'dfor C₁₀H₁₁N₃O₂, 205; found, 205.

Compound 102:(S)-4-(4-((6-oxo-6,6a,7,8-tetrahydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile:(S)-3-(hydroxymethyl)-7,8-dihydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(103 mg, 0.5 mmol), 4-(piperazin-1-yl)benzonitrile (108 mg, 0.575 mmol),(cyanomethyl)trimethylphosphonium iodide (207 mg, 0.850 mmol) andN,N-diisopropylethylamine (0.437 ml, 2.500 mmol) were suspended inPropiononitrile (Volume: 1.502 ml) and heated in a closed vial at 90° C.for 23 h. The reaction mixture was cooled, diluted with MeOH (2 mL) andpurified using preparative HPLC (basic phase). The fractions containingproduct were concentrated in vacuo and crystallized from water-methanol(3 mL, ˜5:1) The precipitate was filtered and dried in vacuum to afford(S)-4-(4-((6-oxo-6,6a,7,8-tetrahydro-5H-azeto[1,2-a]pyrido[3,2-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile(11.7 mg, 0.031 mmol, 6.25% yield) as a light brown solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 2.37-2.47 (m, 4 H) 2.68-2.80 (m, 1 H) 2.94 (tt,J=10.67, 7.26 Hz, 1 H) 3.30 (d, J=4.80 Hz, 4 H) 3.36 (s, 2 H) 3.87-4.00(m, 1 H) 4.21 (q, J=7.66 Hz, 1 H) 4.93 (t, 1 H) 6.98 (d, J=1.77 Hz, 1 H)7.00 (d, J=9.09 Hz, 2 H) 7.57 (d, J=9.09 Hz, 2 H) 7.65 (d, J=1.77 Hz, 1H) 10.34 (s, 1 H). [M+H] calc'd for C₂₁H₂₂N₆O, 374; found, 374.

Compound 103:4-(4-((6-oxo-6,7,7a,8,9,10-hexahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-3-yl)methyl)piperazin-1-yl)benzonitrile

Compound 103A: Methyl6-(2-(2-tert-butoxy-2-oxoethyl)pyrrolidin-1-yl)-5-nitronicotinate:Tert-butyl 2-(pyrrolidin-2-yl)acetate (1.00 g, 5.40 mmol) was added to asolution of methyl 6-chloro-5-nitronicotinate (1.169 g, 5.40 mmol) inTHF (Volume: 10 ml). The reaction mixture was stirred at rt for 1 h andK₂CO₃ (0.760 g, 5.50 mmol) was added. The reaction mixture was stirredfor 2 h and triethylamine (0.379 ml, 2.70 mmol) was added. The mixturewas stirred for 1 h, filtered and concentrated in vacuo. Flash columnchromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 9:1)afforded methyl6-(2-(2-tert-butoxy-2-oxoethyl)pyrrolidin-1-yl)-5-nitronicotinate (1.79g, 4.90 mmol, 91% yield) as a yellow oil. [M+H] calc'd for C₁₇H₂₃N₃O₆,365; found, 365.

Compound 103B: Methyl6-oxo-6,7,7a,8,9,10-hexahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepine-3-carboxylate:Methyl 6-(2-(2-tert-butoxy-2-oxoethyl)pyrrolidin-1-yl)-5-nitronicotinate(1.79 g, 4.90 mmol) was dissolved in dichloromethane (Volume: 24.49 ml)and to this solution was added triphenyl phosphite (0.015 g, 0.049mmol), ammonium metavanadate (0.034 g, 0.294 mmol) and Pt/C (5% wt.)(0.191 g, 0.049 mmol). The reaction mixture was hydrogenated at 100 psiat 25° C. for 3 h. The reaction mixture was filtered through a shortplug of celite and the plug and precipitate were washed well withdichloromethane (30 mL). The combined filtrates were concentrated invacuo and dissolved in AcOH (7 mL). This solution was heated to 90° C.for 10 min and concentrated in vacuo. The residue was crystallized withethyl ether (20 mL) and sonicated until a fine suspension was obtainedThe precipitate was filtered off and dried in vacuum to afford methyl6-oxo-6,7,7a,8,9,10-hexahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepine-3-carboxylate(0.927 g, 3.55 mmol, 72.4% yield) as a light pink solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 1.55-1.71 (m, 1 H) 1.74-1.89 (m, 1 H) 1.89-1.99 (m,1 H) 2.19 (d, J=5.81 Hz, 1 H) 2.59 (dd, J=14.78, 1.64 Hz, 1 H) 2.77 (dd,J=14.78, 9.98 Hz, 1 H) 3.56-3.67 (m, 1 H) 3.67-3.76 (m, 1 H) 3.78 (s, 3H) 3.99 (td, J=9.85, 5.56 Hz, 1 H) 7.64 (d, J=2.02 Hz, 1 H) 8.40 (d,J=2.02 Hz, 1 H) 9.73 (d, 1 H) [M+H] calc'd for C₁₃H₁₅N₃O₃, 261; found,261.

Compound 103C:3-(Hydroxymethyl)-7a,8,9,10-tetrahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one:Methyl6-oxo-6,7,7a,8,9,10-hexahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepine-3-carboxylate(0.900 g, 3.44 mmol) was suspended in THF (Volume: 11.48 ml) undernitrogen atmosphere and NaH (276 mg, 6.9 mmol) was added in severalportions over 2 min. The reaction mixture was stirred at roomtemperature for 10 min and cooled to below −50° C. aluminum(III) lithiumhydride (3.10 ml, 6.20 mmol) was added over the period of 5 min and thereaction was kept at a temperature between −30 and −20° C. for 1 h(LCMS: >95% conversion). The mixture was cooled to below −50° C. andMeOH (4 mL) was added. Water (1 mL) was added and the reaction mixturewas stirred at rt for 10 min. Rochelle salt (20% solution) was added (10mL) and the mixture was extracted with THF (4×10 mL). The combinedorganic extracts were dried (Na2SO4 and MgSO4), filtered andconcentrated in vacuo. The residue was recrystallized from THF/Ethylether (1:1, 20 mL). The solid was filtered off and dried in vacuum toafford3-(hydroxymethyl)-7a,8,9,10-tetrahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one(0.654 g, 2.80 mmol, 81% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.58 (m, J=11.62, 11.62, 9.73, 6.69 Hz, 1 H) 1.74-1.85(m, 1 H) 1.86-1.96 (m, 1 H) 2.14 (m, J=11.91, 5.98, 5.98, 1.89 Hz, 1 H)2.52-2.58 (m, 1 H) 2.58-2.67 (m, 1 H) 3.49 (ddd, J=10.93, 8.15, 2.15 Hz,1 H) 3.66 (td, J=10.61, 6.82 Hz, 1H) 3.81-3.93 (m, 1 H) 4.31 (d, J=5.31Hz, 2 H) 5.01 (t, J=5.43 Hz, 1 H) 7.14 (d, J=2.02 Hz, 1 H) 7.77 (d,J=2.02 Hz, 1 H) 9.60 (d, 1 H). [M+H] calc'd for C₁₂H₁₅N₃O₂, 233; found,233.

Compound 103:4-(4-((6-oxo-6,7,7a,8,9,10-hexahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-3-yl)methyl)piperazin-1-yl)benzonitrile:4-(4-((6-oxo-6,7,7a,8,9,10-hexahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-3-yl)methyl)piperazin-1-yl)benzonitrile:3-(hydroxymethyl)-7a,8,9,10-tetrahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one(100 mg, 0.429 mmol), 4-(piperazin-1-yl)benzonitrile (96 mg, 0.514mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.685 mmol) andN,N-diisopropylethylamine (0.374 mL, 2.141 mmol) were suspended inpropiononitrile (Volume: 2 mL) and heated in a closed vial at 90° C. for5 h. The reaction mixture was cooled, diluted with DMSO (2 mL) andpurified using preparative HPLC (basic phase, 25-95% ACN). The fractionscontaining product were concentrated in vacuo and crystallized fromwater (5 mL). The precipitate was filtered and dried in vacuum to afford4-(4-((6-oxo-6,7,7a,8,9,10-hexahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-3-yl)methyl)piperazin-1-yl)benzonitrile(124.2 mg, 0.309 mmol, 72.1% yield) as a light brown solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 1.51-1.65 (m, 1 H) 1.72-1.86 (m, 1 H) 1.87-1.97 (m,1 H) 2.14 (qd, J=5.81, 4.04 Hz, 1 H) 2.40-2.48 (m, 4 H) 2.52-2.59 (m, 1H) 2.66 (dd, 1 H) 3.30 (br. s., 4 H) 3.33-3.40 (m, 2 H) 3.45-3.54 (m, 1H) 3.66 (td, J=10.61, 6.82 Hz, 1 H) 3.88 (td, J=9.47, 6.06 Hz, 1 H) 7.00(d, J=9.35 Hz, 2 H) 7.14 (d, J=2.02 Hz, 1 H) 7.57 (d, J=9.09 Hz, 2 H)7.75 (d, J=2.02 Hz, 1 H) 9.56 (d, 1 H). [M+H] calc'd for C₂₃H₂₆N₆O, 402;found, 402.

Compound 104:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-7a,8,9,10-tetrahydro-5H-pyrido[3,2-b]pyrrolo[1,2-d][1,4]diazepin-6(7H)-one

Compound 104 was prepared using a procedure analogous to that describedin connection with compound 103, except that1-(4-chlorophenyl)piperazine hydrochloride was used instead of1-(4-ccyanophenyl)piperazine hydrochloride. ¹H NMR (400 MHz, DMSO-d6) δppm 1.51-1.65 (m, 1 H) 1.70-1.87 (m, 1 H) 1.87-1.98 (m, 1 H) 2.09-2.21(m, 1 H) 2.40-2.48 (m, 4 H) 2.55 (d, 1 H) 2.66 (dd, 1 H) 3.04-3.15 (m, 4H) 3.34 (dd, 2 H) 3.46-3.55 (m, 1 H) 3.66 (td, J=10.55, 6.69 Hz, 1 H)3.88 (td, J=9.35, 6.06 Hz, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 7.14 (d, J=1.77Hz, 1 H) 7.21 (d, J=9.09 Hz, 2 H) 7.76 (d, J=1.77 Hz, 1 H) 9.55 (br. s.,1 H). [M+H] calc'd for C₂₃H₂₆ClN₅O, 411; found, 411.

Compound 105:4-((S)-3-methyl-4-((R)-6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

Compound 105A: (S)-tert-butyl4-(4-cyanophenyl)-2-methylpiperazine-1-carboxylate: (S)-tert-butyl2-methylpiperazine-1-carboxylate (1 g, 4.99 mmol), 4-fluorobenzonitrile(0.605 g, 4.99 mmol), and K₂CO₃ (0.897 g, 6.49 mmol) were combined intoa vial equipped with a stir bar. The reaction was heated to 110° C. for48 h. Cooled to RT, diluted with EA and filtered. Concentrated to aclear oil and purified on silica gel (80 g, 10-20% EA in Hex) to give aclear oil (450 mg, 30% yield) which became a crystalline solid uponsitting. [M+H] calc'd for C₁₇H₂₃N₃O₂, 301; found, 301.

Compound 105B: (S)-4-(3-methylpiperazin-1-yl)benzonitrile hydrochloride:(S)-tert-butyl 4-(4-cyanophenyl)-2-methylpiperazine-1-carboxylate (0.404g, 1.340 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirredfor 30 min. The thick white precipitate that formed was diluted withethyl ether (10 mL) and stirred until a fine suspension resulted. Theprecipitate was filtered under nitrogen and dried in vacuum to afford awhite solid (300 mg, 94%). [M+H] calc'd for C₁₂H₁₅N₃, 201; found, 201.

Compound 105:4-((S)-3-methyl-4-(((R)-6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile:To a suspension of(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one(100 mg, 0.617 mmol) in propiononitrile (1.2 mL) was added(cyanomethyl)trimethylphosphonium iodide (180 mg, 0.74 mmol) and DIEA(0.323 ml, 1.80 mmol) and finally(S)-4-(3-methylpiperazin-1-yl)benzonitrile hydrochloride (0.147 g, 0.617mmol). The vial was heated to 90° C. for 16 hours. The crude rxn wascooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90,basic) to give the product as a tan solid (58 mg, 22% yield). ¹H NMR(400 MHz, DMSO-d6) δ ppm 10.62 (s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.56 (d,J=9.1 Hz, 2H), 6.92-7.11 (m, 3H), 4.87 (dt, J=13.6, 2.7 Hz, 1H), 4.25(dd, J=10.9, 3.0 Hz, 1H), 3.84 (d, J=13.4 Hz, 1H), 3.66 (d, J=10.6 Hz,1H), 3.58 (d, J=12.6 Hz, 1H), 2.87-3.12 (m, 3H), 2.64-2.83 (m, 5H),2.39-2.48 (m, 2H), 2.06-2.19 (m, 1H), 1.14 (d, J=6.1 Hz, 3H). [M+H]calc'd for C₂₃H₂₆N₆OS, 434; found, 434.

Compound 106:(R)-N-ethyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

To a suspension of(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one(146 mg, 0.581 mmol) in propiononitrile (1.2 mL) was added(cyanomethyl)trimethylphosphonium iodide (169 mg, 0.697 mmol) andN-ethyl-3-fluoro-4-(piperazin-1-yl)benzamide hydrochloride (167 mg,0.581 mmol) and DIEA (304 μl, 1.743 mmol)). The vial was heated to 90°C. for 16 hours. The crude rxn was cooled to RT, DMSO (1 ml) was added,and purified via HPLC (55-90, basic). The fractions were collected,concentrated until a precipitate was visible and filtered. The solidswere washed with water and collected to retrieve the product as a whitesolid (97 mg, 34% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.66 (s, 1H),8.35 (t, J=5.6 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.55-7.65 (m, 2H),6.97-7.08 (m, 2H), 4.88 (dt, J=13.6, 2.7 Hz, 1H), 4.27 (dd, J=10.9, 3.0Hz, 1H), 3.38 (d, J=2.0 Hz, 2H), 3.20-3.30 (m, 2H), 2.95-3.15 (m, 5H),2.65-2.87 (m, 3H), 2.51 (br. s., 4H), 2.45 (dd, J=13.4, 1.8 Hz, 1H),1.09 (t, J=7.2 Hz, 3H). [M+H] calc'd for C₂₄H₂₉FN₆O₂S, 484; found, 484.

Compound 107:(R)-3-chloro-N-ethyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 107A: 3-chloro-4-fluoro-N-ethylbenzamide: Using ethanaminehydrochloride and 3-chloro-4-fluorobenzoic acid in the general procedurefor coupling of amines to carboxylic acids, the title compound wasobtained (77% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.12 (t, J=7.20 Hz, 3 H) 3.28 (qd, J=7.16, 5.56 Hz, 2 H) 7.53 (t,J=8.84 Hz, 1 H) 7.87 (ddd, J=8.72, 4.80, 2.15 Hz, 1 H) 8.06 (dd, J=7.33,2.27 Hz, 1 H) 8.61 (t, J=4.67 Hz, 1 H). ESI-MS: m/z 202.0 (M+H)⁺.mp=101.7-101.8° C.

Compound 107B: 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide: Using3-chloro-4-fluoro-N-ethylbenzamide in the general procedure fornucleophilic aromatic substitution reactions, the title compound wasobtained (74% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.10 (t, J=7.20 Hz, 3 H) 2.24 (br. s., 1 H) 2.81-2.87 (m, 4 H)2.90-2.98 (m, 4 H) 3.26 (qd, J=7.24, 5.56 Hz, 2 H) 7.15 (d, J=8.59 Hz, 1H) 7.77 (dd, J=8.34, 2.02 Hz, 1 H) 7.87 (d, J=2.27 Hz, 1 H) 8.43 (t,J=5.56 Hz, 1 H). ESI-MS: m/z 268.2 (M+H)⁺. mp=117.3-118.7° C.

Compound 107:(R)-3-chloro-N-ethyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:To a suspension of(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one(154 mg, 0.613 mmol) in propiononitrile (1.2 mL) was added(cyanomethyl)trimethylphosphonium iodide (179 mg, 0.735 mmol) and3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide hydrochloride (186 mg,0.613 mmol) and DIEA (321 μl, 1.838 mmol). The vial was heated to 90° C.for 16 hours. The crude rxn was cooled to RT, DMSO (1 ml) was added, andpurified via HPLC (55-90, basic). The fractions were collected,concentrated until a precipitate was visible and filtered. The solidswere washed with water and collected to retrieve the product as a whitesolid (80 mg, 26% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1H),8.43 (t, J=5.6 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.6, 2.0 Hz,1H), 7.70 (d, J=2.0 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.01 (d, J=2.0 Hz,1H), 4.88 (dt, J=13.6, 2.7 Hz, 1H), 4.27 (dd, J=10.7, 3.2 Hz, 1H), 3.40(s, 2H), 3.18-3.30 (m, 2H), 2.90-3.16 (m, 5H), 2.67-2.85 (m, 3H), 2.52(br. s., 4H), 2.45 (dd, J=13.5, 1.6 Hz, 1H), 1.10 (t, J=7.2 Hz, 3H).[M+H] calc'd for C₂₄H₂₉ClN₆O₂S, 501; found, 501.

Compound 108:(R)-3-chloro-N-methyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 108A: 3-chloro-4-fluoro-N-methylbenzamide: To a suspension of3-chloro-4-fluorobenzoic acid (25.0 g, 143 mmol), Methylaminehydrochloride (11.60 g, 172 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (41.2 g, 215 mmol), and 1H-benzo[d][1,2,3]triazol-1-olhydrate (32.9 g, 215 mmol) in DMF (Volume: 150 mL) was added4-methylmorpholine (79 mL, 716 mmol) at 23° C. The reaction was stirredat 23° C. for 3 hr. The reaction mixture was diluted with water (500 mL)to furnish a yellow-orange solution. The solution was stirred overnightat 23° C. affording a suspension. The suspension was filtered, washedwith H2O (3×100 mL), and the resulting solid was dried in vacuo at 30°C. to provide 3-chloro-4-fluoro-N-methylbenzamide (14.24 g, 76 mmol,53.0% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.78(d, J=4.55 Hz, 3 H) 7.53 (t, J=8.97 Hz, 1 H) 7.86 (ddd, J=8.59, 4.80,2.27 Hz, 1 H) 8.04 (dd, J=7.20, 2.15 Hz, 1 H) 8.51-8.65 (m, 1 H).ESI-MS: m/z 188.0 (M+H)⁺. Mp=108.3-110.0° C.

Compound 108B: 3-chloro-N-methyl-4-(piperazin-1-yl)benzamide: Using3-chloro-4-fluoro-N-methylbenzamide in the general procedure fornucleophilic aromatic substitution reactions, the title compound wasobtained (29% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.59-2.70 (m, 2 H) 2.73-2.79 (m, 3 H) 2.87-2.93 (m, 2 H) 2.95-3.01 (m, 2H) 3.03-3.11 (m, 2 H) 3.23-4.03 (m, 1 H) 7.14-7.23 (m, 1 H) 7.77 (dd,J=8.46, 2.15 Hz, 1 H) 7.85-7.90 (m, 1 H) 8.38-8.48 (m, 1 H). ESI-MS: m/z254.2 (M+H)⁺. mp=176.4-189.1° C.

Compound 108:(R)-3-chloro-N-methyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:To a suspension of(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one(97 mg, 0.386 mmol) in propiononitrile (1.2 mL) was added(cyanomethyl)trimethylphosphonium iodide (113 mg, 0.463 mmol) and3-chloro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (112 mg,0.386 mmol) and DIEA (202 μl, 1.158 mmol). The vial was heated to 90° C.for 16 hours. The crude rxn was cooled to RT, DMSO (1 ml) was added, andpurified via HPLC (55-90, basic). The fractions were collected,concentrated until a precipitate was visible and filtered. The solidswere washed with water and collected to retrieve the product as a whitesolid (21 mg, 11% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1H),8.41 (d, J=4.5 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.6, 2.0 Hz,1H), 7.70 (d, J=1.8 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.00 (d, J=2.0 Hz,1H), 4.88 (ddd, J=13.5, 2.7, 2.5 Hz, 1H), 4.27 (dd, J=10.6, 3.0 Hz, 1H),3.40 (s, 2H), 2.92-3.14 (m, 5H), 2.64-2.85 (m, 6H), 2.51-2.64 (m, 3H),2.45 (dd, J=13.4, 1.5 Hz, 2H). [M+H] calc'd for C₂₃H₂₇ClN₆O₂S, 487;found, 487.

Compound 109:(S)-N-ethyl-3-fluoro-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

To a suspensionof(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(83 mg, 0.355 mmol) in propiononitrile (1.2 mL) was added(cyanomethyl)trimethylphosphonium iodide (104 mg, 0.426 mmol) and DIEA(0.186 ml, 1.066 mmol) and finallyN-ethyl-3-fluoro-4-(piperazin-1-yl)benzamide (102 mg, 0.355 mmol). Thevial was heated to 90° C. for 16 hours. The crude rxn was cooled to RT,DMSO (1 ml) was added, and purified via HPLC (55-90, basic). Thefractions were collected, concentrated until a precipitate was visibleand filtered. The solids were washed with water and collected toretrieve the product as a white solid (50 mg, 30% yield). ¹H NMR (400MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 8.35 (t, J=5.4 Hz, 1H), 7.49-7.72 (m,3H), 6.87-7.15 (m, 2H), 4.50 (d, J=12.9 Hz, 1H), 3.84 (dd, J=11.4, 2.8Hz, 1H), 3.40 (d, J=2.8 Hz, 2H), 3.18-3.30 (m, 2H), 3.08 (br. s., 4H),2.60 (td, J=12.6, 2.5 Hz, 1H), 2.49 (br. s., 4H), 2.03 (d, J=12.9 Hz,1H), 1.77-1.91 (m, 1H), 1.64 (d, J=12.9 Hz, 1H), 1.32-1.57 (m, 3H), 1.09(t, J=7.2 Hz, 3H). [M+H] calc'd for C₂₅H₃₁FN₆O₂, 467; found, 467.

Compound 110:(S)-3-chloro-N-ethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

To a suspension of(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(81 mg, 0.347 mmol) in propiononitrile (1.2 mL) was added(cyanomethyl)trimethylphosphonium iodide (101 mg, 0.417 mmol) and DIEA(182 μl, 1.042 mmol) and finally3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide hydrochloride (106 mg,0.347 mmol). The vial was heated to 90° C. for 16 hours. The crude rxnwas cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90,basic). The fractions were collected, concentrated until a precipitatewas visible and filtered. The solids were washed with water andcollected to retrieve the product as a white solid (70 mg, 20% yield).¹H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 8.43 (t, J=5.4 Hz, 1H),7.87 (d, J=2.3 Hz, 1H), 7.76 (dd, J=8.3, 2.0 Hz, 1H), 7.66 (d, J=1.8 Hz,1H), 7.17 (d, J=8.6 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 4.50 (d, J=12.9 Hz,1H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.38 (s, 2H), 3.18-3.31 (m, 2H),3.03 (br. s., 4H), 2.60 (td, J=12.7, 2.7 Hz, 1H), 2.51 (br. s., 4H),2.04 (d, J=12.9 Hz, 1H), 1.85 (d, J=12.1 Hz, 1H), 1.64 (d, J=12.6 Hz,1H), 1.32-1.58 (m, 3H), 1.10 (t, J=7.1 Hz, 3H). [M+H] calc'd forC₂₅H₃₁ClN₆O₂, 483; found, 483.

Compound 111:(S)-3-chloro-N-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

To a suspension of(S)-3-((S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(111 mg, 0.476 mmol) in propiononitrile (1.2 mL) was added(cyanomethyl)trimethylphosphonium iodide (139 mg, 0.571 mmol) and DIEA(249 μl, 1.428 mmol) and finally3-chloro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (138 mg,0.476 mmol). The vial was heated to 90° C. for 16 hours. The crude rxnwas cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90,basic). The fractions were collected, concentrated until a precipitatewas visible and filtered. The solids were washed with water andcollected to retrieve the product as a white solid (64 mg, 29% yield).¹H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (br. s., 1H), 8.43 (d, J=4.3 Hz,1H), 7.87 (s, 1H), 7.76 (dd, J=8.3, 1.5 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H),7.54-7.74 (m, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.99 (br. s., 1H), 4.52 (d,J=12.6 Hz, 1H), 3.85 (br. s., 1H), 3.44 (br. s., 2H), 2.92 (d, J=4.5 Hz,4H), 2.75 (d, J=4.5 Hz, 4H), 2.52-2.69 (m, 3H), 1.99-2.09 (m, 1H), 1.85(d, J=12.4 Hz, 1H), 1.64 (d, J=12.4 Hz, 1H), 1.32-1.58 (m, 3H). [M+H]calc'd for C₂₄H₂₉ClN₆O₂, 469; found, 469.

Compound 112:(S)-3-fluoro-N-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 112A: 3,4-difluoro-N-methylbenzamide: Using methanaminehydrochloride and 3,4-difluorobenzoic acid in the general procedure forcoupling of amines to carboxylic acids, the title compound was obtained(75% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.78(d, J=4.55 Hz, 3 H) 7.55 (dt, J=10.61, 8.34 Hz, 1 H) 7.72 (dddd, J=8.59,4.55, 2.15, 1.39 Hz, 1 H) 7.86 (ddd, J=11.68, 7.89, 2.15 Hz, 1 H)8.48-8.59 (m, 1 H). ESI-MS: m/z 172.1 (M+H)⁺. mp=142.7-145.0° C.

Compound 112B: 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide: Using3,4-difluoro-N-methylbenzamide in the general procedure for nucleophilicaromatic substitution reactions, the title compound was obtained (43%yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.34 (br. s., 1H) 2.57-2.66 (m, 1 H) 2.72-2.79 (m, 3 H) 2.80-2.88 (m, 3 H) 2.95-3.04(m, 3 H) 3.07-3.16 (m, 1 H) 6.99-7.11 (m, 1 H) 7.52-7.65 (m, 2 H)8.29-8.38 (m, 1 H). ESI-MS: m/z 238.2 (M+H)⁺. mp=174.1-192.9° C.

Compound 112:(S)-3-fluoro-N-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:To a suspension of(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(129 mg, 0.553 mmol) in propiononitrile (1.2 mL) was added((cyanomethyl)trimethylphosphonium iodide (161 mg, 0.664 mmol)) and3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (151 mg,0.553 mmol) and DIEA (290 μl, 1.659 mmol)). The vial was heated to 90°C. for 16 hours. The crude rxn was cooled to RT, DMSO (1 ml) was added,and purified via HPLC (55-90, basic). The fractions were collected,concentrated until a precipitate was visible and filtered. The solidswere washed with water and collected to retrieve the product as a whitesolid (83 mg, 33% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H),8.33 (d, J=4.5 Hz, 1H), 7.45-7.70 (m, 3H), 6.88-7.10 (m, 2H), 4.50 (d,J=12.9 Hz, 1H), 3.83 (dd, J=11.1, 2.5 Hz, 1H), 3.36 (s, 2H), 3.08 (br.s., 4H), 2.75 (d, J=4.5 Hz, 3H), 2.56-2.64 (m, 1H), 2.50 (br. s., 4H),1.97-2.12 (m, 1H), 1.85 (d, J=11.1 Hz, 1H), 1.63 (d, J=11.9 Hz, 1H),1.29-1.57 (m, 3H). [M+H] calc'd for C₂₄H₂₉FN₆O₂, 453; found, 453.

Compound 113:(S)-N,3-dimethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 113A: N,3-dimethyl-4-(piperazin-1-yl)benzamide: To tert-butyl4-(2-methyl-4-(methylcarbamoyl)phenyl)piperazine-1-carboxylate (1.90 g,5.70 mmol) was added Hydrochloric acid solution (17.10 ml, 68.4 mmol) indioxane at 23° C. The reaction was stirred at 23° C. for 30 min. Theresulting suspension was diluted with Et2O (20 mL), filtered, rinsedwith Et2O (3×10 mL), and the resulting solid was dried in vacuo toprovide N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride (1.70g, 5.55 mmol, 97% yield) as an off-white, hygroscopic solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.28 (s, 3 H) 2.72-2.79 (m, 3 H) 3.05-3.14 (m, 4 H)3.17-3.28 (m, 4 H) 7.06 (d, J=8.34 Hz, 1 H) 7.64-7.68 (m, 1 H) 7.68-7.70(m, 1 H) 8.29-8.39 (m, 1 H) 9.36 (br. s., 2 H). ESI-MS: m/z 234.2(M+H)⁺.

Compound 113:(S)-N,3-dimethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(100 mg, 0.429 mmol), N,3-dimethyl-4-(piperazin-1-yl)benzamidedihydrochloride (131 mg, 0.429 mmol), (cyanomethyl)trimethylphosphoniumiodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143mmol) were suspended in propiononitrile (Volume: 1287 μl) and heated ina closed vial at 90° C. for 4 h. The reaction mixture became a darkbrown solution. It was cooled to room temperature and purified usingHPLC (NH4HCO3 buffered, 20-70% ACN in water). The fractions wereconcentrated in vacuo and the resulting solid was recrystallized fromMeCN (5 mL), filtered off, washed with water (2 mL) and dried in vacuumto afford(S)-N,3-dimethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(27.4 mg, 0.061 mmol, 14.25% yield) as a light beige solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.31-1.57 (m, 3 H) 1.64 (d, J=11.87 Hz, 1 H) 1.85(d, J=11.37 Hz, 1 H) 2.04 (d, J=11.87 Hz, 1 H) 2.25 (s, 3 H) 2.51-2.70(m, 5 H) 2.56-2.70 (m, 2 H) 2.74 (d, J=4.29 Hz, 3 H) 2.87 (br. s., 4 H)3.37-3.45 (m, 2 H) 3.84 (dd, J=11.24, 2.40 Hz, 1 H) 4.50 (d, J=13.14 Hz,1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.01 (d, J=8.34 Hz, 1 H) 7.61 (dd, J=8.46,1.64 Hz, 1 H) 7.65 (dd, J=12.25, 1.64 Hz, 2 H) 8.23 (q, J=4.13 Hz, 1 H)10.48 (s, 1 H); [M+H] calc'd for C₂₅H₃₂N₆O₂, 449; found, 449.

Compound 114:(S)-N-ethyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 114A: 3-methyl-4-(piperazin-1-yl)benzonitrile: To a solution of4-fluoro-3-methylbenzonitrile (2.5 g, 18.50 mmol) in DMSO (Volume: 10.0mL) was added piperazine (7.97 g, 92 mmol) at 23° C. The reaction wasstirred at 140° C. for 16 hr. The reaction mixture was poured into H2O(100 mL) and the reaction vessel was rinsed with H2 (−50 mL). Theresulting suspension was filtered, rinsed with H2O (3×10 mL) and theresulting solid was dried in vacuo to provide3-methyl-4-(piperazin-1-yl)benzonitrile (2.593 g, 12.88 mmol, 69.6%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.21-2.30 (m, 3H) 2.57-2.70 (m, 1 H) 2.83 (s, 8 H) 7.03-7.09 (m, 1 H) 7.55-7.62 (m, 2H). ESI-MS: m/z 202.1 (M+H)⁺.

Compound 114B: tert-butyl4-(4-cyano-2-methylphenyl)piperazine-1-carboxylate: To a solution of3-methyl-4-(piperazin-1-yl)benzonitrile (2.533 g, 12.59 mmol) in THF(Ratio: 1.000, Volume: 25 mL) and MeOH (Ratio: 1.000, Volume: 25 mL) wasadded Di-tert-butyl dicarbonate (3.09 mL, 13.47 mmol) at 10° C. Thereaction was stirred at 10° C. for 15 min warmed to 23° C. and stirredat for 18 hr. The resulting suspension was filtered, rinsed with THF(3×5 mL) and the filtrate was concentrated in vacuo. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.42 (s, 9 H) 2.28 (s, 3 H) 2.83-2.92 (m, 4 H) 3.42-3.52(m, 4 H) 7.08-7.13 (m, 1 H) 7.57-7.65 (m, 2 H). ESI-MS: m/z 302.1(M+H)⁺.

Compound 114C: 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methylbenzoicacid: To a suspension of tert-butyl4-(4-cyano-2-methylphenyl)piperazine-1-carboxylate (3.685 g, 12.23 mmol)in EtOH (Ratio: 1.000, Volume: 50 mL) and Water (Ratio: 1.000, Volume:10 mL) was added Sodium hydroxide solution (8.48 mL, 162 mmol) at 23° C.Rinsed sodium hydroxide forward with Water (Ratio: 1.000, Volume: 2.5mL) The reaction was stirred at 90° C. for 10 hr. The reaction mixturewas cooled to 23° C., neutralized with 3N HCl (52 mL), filtered, rinsedwith H2O (3×10 mL), and the resulting solid was dried in vacuo toprovide 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methylbenzoic acid(3.588 g, 11.20 mmol, 92% yield) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.42 (s, 9 H) 2.29 (s, 3 H) 2.81-2.90 (m, 4 H) 3.42-3.53(m, 4 H) 7.05 (d, J=8.08 Hz, 1 H) 7.70-7.77 (m, 2 H) 12.61 (br. s., 1H). ESI-MS: m/z 321.2 (M+H)⁺.

Compound 114D: tert-butyl4-(4-(ethylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate:4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methylbenzoic acid (0.866 g,2.70 mmol), ethanamine hydrochloride (0.264 g, 3.24 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.777 g, 4.05 mmol) and 1H-benzo[d][1,2,3]triazol-1-olhydrate (0.621 g, 4.05 mmol) were suspended in DMF (Volume: 3.68 ml) and4-methylmorpholine (1.486 ml, 13.52 mmol) was added. The reactionmixture was stirred at ambient temperature for 2 h. It was diluted withwater (50 mL) and extracted with ethyl acetate (3×75 mL). The combinedorganic extracts were washed with 1N HCl (aq., 25 mL), NaHCO3 (sat. aq.,25 mL), water (25 mL), brine (25 mL), dried (MgSO4), concentrated invacuo and dried under vacuum to afford tert-butyl4-(4-(ethylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate (0.9327 g,2.68 mmol, 99% yield) as a white solid. ¹H NMR (DMSO-d₆,400 MHz): δ=8.24(t, J=5.4 Hz, 1 H), 7.66 (d, J=1.8 Hz, 2 H), 7.03 (d, J=8.3 Hz, 1 H),3.42-3.52 (m, 4 H), 3.20-3.27 (m, 2 H), 2.78-2.87 (m, 4 H), 2.28 (s, 3H), 1.43 (s, 9 H), 1.10 ppm (t, J=7.2 Hz, 3 H). ESI-MS: m/z 348.4(M+H)⁺.

Compound 114E: N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide: Tert-butyl4-(4-(ethylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate (0.9323 g,2.68 mmol) was diluted with 4.0M HCl in dioxane (8 mL) and stirred for30 min. The thick white precipitate that formed was diluted with ethylether (10 mL) and stirred until a fine suspension resulted. Theprecipitate was filtered under nitrogen, washed with ether (5 mL) anddried in vacuum to afford N-ethyl-3-methyl-4-(piperazin-1-yl)benzamidehydrochloride (0.7528 g, 2.65 mmol, 99% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3 H) 2.29 (s, 3 H)3.00-3.14 (m, 4 H) 3.16-3.32 (m, 6 H) 7.07 (d, J=8.34 Hz, 1 H) 7.62-7.71(m, 2 H) 8.34 (t, J=5.43 Hz, 1 H) 9.17 (br. s., 2 H). ESI-MS: m/z 248.2(M+H)⁺.

Compound 114:(S)-N-ethyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(100 mg, 0.429 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamidehydrochloride (133 mg, 0.469 mmol), (cyanomethyl)trimethylphosphoniumiodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143mmol) were suspended in Propiononitrile (Volume: 1287 μl) and heated ina closed vial at 90° C. for 4 h. The reaction mixture became a darkbrown solution. It was cooled to room temperature and purified usingHPLC (NH4HCO3 buffered, 20-70% ACN in water). The fractions wereconcentrated in vacuo and the resulting solid was slurried with hot MeCN(5 mL), cooled to ambient temperature, filtered off, washed with water(2 mL) and dried in vacuum to afford(S)-N-ethyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(70.3 mg, 0.152 mmol, 35.4% yield) as a light beige solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.09 (t, J=7.20 Hz, 3 H) 1.33-1.57 (m, 3 H) 1.64 (d,J=12.13 Hz, 1 H) 1.85 (d, J=11.37 Hz, 1 H) 2.04 (d, J=12.13 Hz, 1 H)2.26 (s, 3 H) 2.52-2.70 (m, 5 H) 2.87 (br. s., 4 H) 3.19-3.29 (m, 2 H)3.37-3.43 (m, 2 H) 3.84 (dd, J=11.49, 2.65 Hz, 1 H) 4.50 (d, J=12.88 Hz,1 H) 6.98 (d, J=1.52 Hz, 1 H) 7.01 (d, J=8.34 Hz, 1 H) 7.62 (d, J=8.59Hz, 1 H) 7.65 (dd, J=9.35, 1.26 Hz, 2 H) 8.26 (t, J=5.43 Hz, 1 H) 10.49(s, 1 H); [M+H] calc'd for C₂₆H₃₄N₆O₂, 463; found, 463.

Compound 115:(S)-N-cyclopropyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 115A: tert-butyl4-(4-(cyclopropylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate:Cyclopropylamine (0.389 mL, 5.62 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (1.346 g, 7.02 mmol), and 1H-benzo[d][1,2,3]triazol-1-olhydrate (1.075 g, 7.02 mmol) in DMF (Volume: 6.4 mL) was added4-methylmorpholine (2.57 mL, 23.41 mmol) at 23° C. The reaction wasstirred at 23° C. for 2 hr. The reaction mixture was diluted with water(50 mL) and the product was extracted with EtOAc (3×50 mL). The organicextracts were combined, washed with 1N HCl (25 mL), saturated NaHCO3 (25mL), H2O (25 mL), brine (25 mL), dried over MgSO4, filtered, rinsed withEtOAc, and dried in vacuo to provide tert-butyl4-(4-(cyclopropylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate(1.53 g, 4.26 mmol, 91% yield) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.51-0.60 (m, 2 H) 0.60-0.70 (m, 2 H) 1.42 (s, 9 H) 2.28(s, 3 H) 2.77-2.87 (m, 5 H) 3.41-3.53 (m, 4 H) 7.02 (d, J=8.08 Hz, 1 H)7.61 (dd, J=8.21, 1.89 Hz, 1 H) 7.64 (d, J=1.77 Hz, 1 H) 8.25 (d, J=4.29Hz, 1 H). ESI-MS: m/z 360.3 (M+H)⁺. mp=111.0-115.4° C.

Compound 115B: N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide: Totert-butyl4-(4-(cyclopropylcarbamoyl)-2-methylphenyl)piperazine-1-carboxylate(1.490 g, 4.15 mmol) was added Hydrochloric acid solution (8.72 mL, 34.9mmol) in dioxane at 23° C. The reaction was stirred at 23° C. for 30min. The resulting suspension was diluted with Et2O (10 mL), filtered,rinsed with Et2O (3×5 mL), and the resulting solid was dried in vacuo toprovide N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamidedihydrochloride (1.37 g, 4.15 mmol, 100% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.51-0.61 (m, 2 H) 0.61-0.70 (m, 2 H)2.28 (s, 3 H) 2.82 (tq, J=7.41, 3.99 Hz, 1 H) 3.02-3.13 (m, 4 H)3.14-3.29 (m, 4 H) 7.05 (d, J=8.34 Hz, 1 H) 7.62-7.69 (m, 2 H) 8.32 (d,J=4.29 Hz, 1 H) 9.38 (br. s., 2 H). ESI-MS: m/z 260.2 (M+H)⁺.mp=171.5-172.8° C.

Compound 115:(S)-N-cyclopropyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(100 mg, 0.429 mmol), N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamidedihydrochloride (143 mg, 0.430 mmol), (cyanomethyl)trimethylphosphoniumiodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143mmol) were suspended in Propiononitrile (Volume: 1287 μl) and heated ina closed vial at 90° C. for 4 h. The reaction mixture became a darkbrown solution. It was cooled to room temperature and purified usingHPLC (NH4HCO3 buffered, 20-70% ACN in water). The fractions wereconcentrated in vacuo and the resulting solid was recrystallized fromMeCN (20 mL), filtered off, washed with water (2 mL) and dried in vacuumto afford(S)-N-cyclopropyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(50.7 mg, 0.107 mmol, 24.92% yield) as a light brown solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.49-0.59 (m, 2 H) 0.60-0.71 (m, 2 H) 1.33-1.57 (m,3 H) 1.64 (d, J=12.88 Hz, 1 H) 1.85 (d, J=12.63 Hz, 1 H) 2.04 (d,J=12.88 Hz, 1 H) 2.25 (s, 3 H) 2.42-2.56 (m, 4 H) 2.60 (td, J=12.63,2.78 Hz, 1 H) 2.76-2.93 (m, 5 H) 3.38 (s, 2 H) 3.84 (dd, J=11.37, 2.78Hz, 1 H) 4.50 (d, J=13.14 Hz, 1 H) 6.98 (d, J=2.02 Hz, 1 H) 7.00 (d,J=8.34 Hz, 1 H) 7.56-7.63 (m, 2 H) 7.66 (d, J=2.02 Hz, 1 H) 8.22 (d,J=4.29 Hz, 1 H) 10.49 (s, 1 H); [M+H] calc'd for C₂₇H₃₄N₆O₂, 475; found,475.

Compound 116:(S)-N-cyclopropyl-3-fluoro-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 116A: N-cyclopropyl-3,4-difluorobenzamide: Usingcyclopropylamine and 3,4-difluorobenzoic acid in the general procedurefor coupling of amines to carboxylic acids, the title compound wasobtained (89% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.52-0.63 (m, 2 H) 0.63-0.74 (m, 2 H) 2.83 (tq, J=7.42, 3.98 Hz, 1H) 7.52 (dt, J=10.55, 8.37 Hz, 1 H) 7.66-7.75 (m, 1 H) 7.85 (ddd,J=11.68, 7.89, 2.15 Hz, 1 H) 8.42-8.60 (m, 1 H). ESI-MS: m/z 198.1(M+H)⁺. mp=104.1-108.4° C.

Compound 116B: N-cyclopropyl-3-fluoro-4-(piperazin-1-yl)benzamide: UsingN-cyclopropyl-3,4-difluorobenzamide in the general procedure fornucleophilic aromatic substitution reactions, the title compound wasobtained (33% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.51-0.61 (m, 2 H) 0.61-0.71 (m, 2 H) 2.55-2.68 (m, 1 H) 2.71-2.91 (m, 5H) 2.92-3.09 (m, 4 H) 6.97-7.09 (m, 1 H) 7.51-7.65 (m, 2 H) 8.27 (d,J=4.04 Hz, 1 H). ESI-MS: m/z 264.2 (M+H)⁺. mp=140.9-143.1° C.

Compound 116:(S)-N-cyclopropyl-3-fluoro-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(150 mg, 0.643 mmol), N-cyclopropyl-3-fluoro-4-(piperazin-1-yl)benzamide(203 mg, 0.772 mmol), (cyanomethyl)trimethylphosphonium iodide (250 mg,1.029 mmol) and N,N-diisopropylethylamine (562 μl, 3.22 mmol) weresuspended in Propiononitrile (Volume: 1931 μl) and heated in a closedvial at 100° C. for 4 h. The reaction mixture became a dark brownsolution with precipitate. It was cooled to room temperature and theprecipitate was filtered off, washed with MeCN (2 mL) and suspended inMeCN with heating and sonication. The suspension was cooled to ambienttemperature, and the precipitate was filtered off, washed with MeCN (2mL) and dried in vacuum to afford(S)-N-cyclopropyl-3-fluoro-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(265 mg, 0.554 mmol, 86% yield) as a white solid. ¹H NMR (DMSO-d₆) δ10.48 (s, 1H), 8.31 (d, J=4.3 Hz, 1H), 7.53-7.69 (m, 4H), 7.02 (t, J=8.8Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 4.50 (br. d, J=12.9 Hz, 1H), 3.84 (dd,J=11.2, 2.7 Hz, 1H), 3.37 (s, 2H), 3.01-3.13 (m, 4H), 2.80 (tq, J=7.4,3.9 Hz, 1H), 2.60 (td, J=12.6, 2.5 Hz, 1H), 2.44-2.51 (m, 4H), 2.04 (br.d, J=12.9 Hz, 1H), 1.85 (br. d, J=12.4 Hz, 1H), 1.64 (br. d, J=12.6 Hz,1H), 1.33-1.56 (m, 3H), 0.61-0.71 (m, 2H), 0.50-0.60 (m, 2H); [M+H]calc'd for C₂₆H₃₁FN₆O₂, 479; found, 479.

Compound 117:(S)-3-chloro-N-cyclopropyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 117A: 3-chloro-N-cyclopropyl-4-fluorobenzamide: Usingcyclopropylamine and 3-chloro-4-fluorobenzoic acid in the generalprocedure for coupling of amines to carboxylic acids, the title compoundwas obtained (89% yield) as a white solid. ¹H NMR (DMSO-d₆,400 MHz):δ=8.56 (d, J=3.5 Hz, 1 H), 8.03 (dd, J=7.3, 2.3 Hz, 1 H), 7.85 (ddd,J=8.6, 4.8, 2.3 Hz, 1 H), 7.52 (t, J=9.0 Hz, 1 H), 2.83 (tq, J=7.4, 3.9Hz, 1 H), 0.66-0.75 (m, 2 H), 0.53-0.61 ppm (m, 2 H). ESI-MS: m/z 214.0(M+H)¹.

Compound 117B: 3-chloro-N-cyclopropyl-4-(piperazin-1-yl)benzamide: Using3-chloro-N-cyclopropyl-4-fluorobenzamide in the general procedure fornucleophilic aromatic substitution reactions, the title compound wasobtained (77% yield) as a white solid. ESI-MS: m/z 280.2 (M+H)¹.

Compound 117:(S)-3-chloro-N-cyclopropyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(150 mg, 0.643 mmol), 3-chloro-N-cyclopropyl-4-(piperazin-1-yl)benzamide(216 mg, 0.772 mmol), (cyanomethyl)trimethylphosphonium iodide (250 mg,1.029 mmol) and N,N-diisopropylethylamine (562 μl, 3.22 mmol) weresuspended in Propiononitrile (Volume: 1931 μl) and heated in a closedvial at 100° C. for 4 h. The reaction mixture became a dark brownsolution with a precipitate. It was cooled to room temperature and theprecipitate was filtered off, washed with MeCN (2 mL) and suspended inMeCN (15 mL) with heating and sonication. It was then cooled to ambienttemperature, the precipitate was filtered off, washed with MeCN (2 mL)and dried in vacuum to afford(S)-3-chloro-N-cyclopropyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(272.4 mg, 0.550 mmol, 86% yield) as a white solid. ¹H NMR (DMSO-d₆) δ10.49 (s, 1H), 8.39 (d, J=4.3 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.75 (dd,J=8.3, 2.0 Hz, 1H), 7.66 (s, 1H), 7.16 (d, J=8.6 Hz, 1H), 6.97 (d, J=1.8Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.38(s, 2H), 3.02 (br. s., 4H), 2.77-2.88 (m, J=0.8 Hz, 1H), 2.60 (td,J=12.6, 2.5 Hz, 1H), 2.49-2.55 (m, J=3.5, 1.8, 1.8 Hz, 4H), 2.04 (br. d,J=12.6 Hz, 1H), 1.86-1.87 (m, OH), 1.84 (br. s., 1H), 1.64 (br. d,J=12.6 Hz, 1H), 1.32-1.57 (m, 3H), 0.61-0.72 (m, 2H), 0.51-0.61 (m, 2H);[M+H] calc'd for C₂₆H₃₁ClN₆O₂, 495; found, 495.

Compound 118:(S)-3-methoxy-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(150 mg, 0.643 mmol), 3-methoxy-4-(piperazin-1-yl)benzonitrilehydrochloride (163 mg, 0.643 mmol), (cyanomethyl)trimethylphosphoniumiodide (250 mg, 1.029 mmol) and N,N-diisopropylethylamine (562 μl, 3.22mmol) were suspended in Propiononitrile (Volume: 1931 μl) and heated ina closed vial at 100° C. for 2 h. The reaction mixture became a darkbrown solution. It was diluted with MeCN (4 mL) and concentrated invacuo to about 3 mL. The resulting precipitate was filtered,recrystallized from MeCN (5 mL) and dried in vacuum to afford(S)-3-methoxy-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile(125 mg, 0.289 mmol, 44.9% yield) as an off-white solid. ¹H NMR(DMSO-d₆) δ 10.48 (s, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.30-7.36 (m, 2H),6.93-6.98 (m, 2H), 4.50 (d, J=12.9 Hz, 1H), 3.79-3.87 (m, 4H), 3.34-3.40(m, 2H), 3.07 (br. s., 4H), 2.60 (td, J=12.7, 2.7 Hz, 1H), 2.47 (br. s.,4H), 2.02 (br. s., 1H), 1.85 (d, J=12.1 Hz, 1H), 1.64 (d, J=12.4 Hz,1H), 1.32-1.57 (m, 3H); [M+H] calc'd for C₂₄H₂₈N₆O₂, 433; found, 433.

Compound 119:N-ethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(50 mg, 0.214 mmol), N-ethyl-4-(piperazin-1-yl)benzamide (55.0 mg, 0.236mmol), (cyanomethyl)trimethylphosphonium iodide (67.7 mg, 0.279 mmol)and N,N-diisopropylethylamine (187 μl, 1.072 mmol) were suspended inPropiononitrile (Volume: 644 μl) and heated in a closed vial at 90° C.for 1 h. It was cooled to ambient temperature, the resulting precipitatewas filtered, washed with MeCN (5 mL) and dried in vacuum to affordN-ethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(56 mg, 0.125 mmol, 58.2% yield) as a white solid. ¹H NMR (DMSO-d₆) δ10.43 (s, 1H), 8.12 (t, J=5.6 Hz, 1H), 7.70 (d, J=9.1 Hz, 2H), 7.66 (d,J=2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.47-4.55(m, 1H), 3.83 (dd, J=11.4, 2.8 Hz, 1H), 3.32-3.40 (m, 2H), 3.18-3.28 (m,6H), 2.61 (td, J=12.6, 2.5 Hz, 1H), 2.43-2.49 (m, 4H), 2.04 (d, J=13.1Hz, 1H), 1.80-1.91 (m, 2H), 1.64 (d, J=12.6 Hz, 2H), 1.33-1.58 (m, 3H),1.09 (d, J=14.4 Hz, 3H); [M+H] calc'd for C₂₅H₃₂N₆O₂, 449; found, 449.

Compound 120:(6aS)-3-((2-methyl-4-(pyridin-2-yl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 120 was prepared using a procedure analogous to that describedin connection with compound 1, except that3-methyl-1-(pyridin-2-yl)piperazine was used instead of1-(4-chlorophenyl)piperazine hydrochloride. [M+H] calc'd for C₂₁H₂₆N₆O,379; found, 379.

Compound 121: (S)-ethyl6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinate

Compound 121 was prepared using a procedure analogous to that describedin connection with compound 1, except that ethyl6-(piperazin-1-yl)nicotinate was used instead of1-(4-chlorophenyl)piperazine hydrochloride. [M+H] calc'd for C₂₃H₂₈N₆O₃,437; found, 437.

Compound 122:(S)-3-((1-(4-chlorophenyl)piperidin-4-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 122A: (S)-ethyl1-(5-bromo-3-nitropyridin-2-yl)pyrrolidine-2-carboxylate:5-bromo-2-chloro-3-nitropyridine (5.94 g, 25 mmol) and (S)-ethylpyrrolidine-2-carboxylate (7.52 g, 52.5 mmol) were combined and stirredat 90° C. for 10 min in a closed vial. The crude material was purifiedby flash column chromatography (20-30% EtOAc in hexanes to afford(S)-ethyl 1-(5-bromo-3-nitropyridin-2-yl)pyrrolidine-2-carboxylate (8.43g, 24.49 mmol, 98% yield) as a yellow viscous oil. [M+H] calc'd forC₁₂H₁₄BrN₃O₄, 344; found, 344.

Compound 122B:(S)-3-bromo-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one:(S)-ethyl 1-(5-bromo-3-nitropyridin-2-yl)pyrrolidine-2-carboxylate (8.6g, 24.99 mmol) was dissolved in dichloromethane (Volume: 125 ml) and tothis solution was added triphenyl phosphite (0.078 g, 0.250 mmol),ammonium metavanadate (0.175 g, 1.499 mmol) and Pt/C (5% wt.) (0.975 g,0.250 mmol). The reaction mixture was hydrogenated at 80 psi at 25° C.for 4 h. The reaction mixture was filtered through celite using DCM andMeOH to complete the transfer and wash the celite plug. The combinedfiltrates and washes were concentrated in vacuo and crystallized withethyl ether (75 mL). The precipitate was filtered and dried in vacuum toafford(S)-3-bromo-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(2.87 g, 10.70 mmol, 42.8% yield) as a pale beige solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 1.82-2.03 (m, 3 H) 2.11-2.26 (m, 1 H) 3.27-3.47 (m,1 H) 3.49-3.63 (m, 1 H) 4.01-4.11 (m, 1 H) 7.06 (d, J=2.27 Hz, 1 H) 7.77(d, J=2.02 Hz, 1 H) 10.57 (s, 1 H). [M+H] calc'd for C₁₀H₁₀BrN₃O, 268;found, 268.

Compound 122C: 1-(4-chlorophenyl)-4-methylenepiperidine:Methyltriphenylphosphonium bromide (1.429 g, 4.00 mmol) was suspended inTHF (Ratio: 1.667, Volume: 2.5 ml) and cooled to −78° C. n-butyllithium(0.960 ml, 2.400 mmol) was added dropwise over 3 min and the resultingyellow suspension was stirred at −78° C. for 10 min. A solution of1-(4-chlorophenyl)piperidin-4-one (0.419 g, 2 mmol) in THF (Ratio:1.000, Volume: 1.5 ml) was added dropwise over 3 min and the dark redsuspension was stirred at −78° C. for 10 min and then allowed to slowlywarm to 5° C. over 1 h. The reaction was stirred at 5° C. for 4 h andwas quenched with water (4 mL). This was extracted with ethyl ether (2×5mL) and the extracts were washed with water (4×5 mL). The combined waterwashes were back-extracted with ethyl ether (5 mL) and the combinedorganic extracts were washed with brine (5 ml), dried (MgSO4), filteredand concentrated in vacuo. Flash column chromatography (40 g SiO₂,hexanes:ethyl acetate 9:1) afforded1-(4-chlorophenyl)-4-methylenepiperidine (0.196 g, 0.944 mmol, 47.2%yield) as a clear yellow oil. [M+H] calc'd for C₁₂H₁₄C1, 208; found,208.

Compound 122:(S)-3-((1-(4-chlorophenyl)piperidin-4-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one:1-(4-chlorophenyl)-4-methylenepiperidine (70 mg, 0.337 mmol) was dilutedwith 0.5M THF solution of 9-BBN (0.674 mL, 0.337 mmol) under nitrogenand stirred at 75° C. for 1 h. The reaction mixture was then added to asuspension of(S)-3-bromo-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(90 mg, 0.337 mmol), PdCl2(dppf)-CH2Cl2 adduct (8.26 mg, 10.11 μmol) andpotassium carbonate (93 mg, 0.674 mmol) in DMF (1.0 mL) and water (0.1mL) and stirred at 60° C. for 4 h.

The mixture was cooled, diluted with water (10 mL) and the resulting redmaterial was separated off, washed with water, dissolved in ethylacetate (10 mL), dried (MgSO4), filtered and concentrated in vacuo.Flash column chromatography (12 g SiO2, ethyl acetate) provided thedesired product as a yellow solid. It was suspended in MeOH (5 mL) andthe precipitate was filtered and dried in vacuo to give the product as awhite solid (16 mg, 12% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm1.11-1.30 (m, 2 H) 1.43-1.58 (m, 0 H) 1.63 (d, J=12.13 Hz, 1 H)1.80-2.03 (m, 2 H) 2.06-2.25 (m, 1 H) 2.29-2.44 (m, 2 H) 2.53-2.64 (m, 2H) 3.35-3.44 (m, 1 H) 3.51-3.62 (m, 1 H) 3.65 (d, J=12.13 Hz, 2 H)3.87-3.98 (m, 1 H) 6.82 (d, J=1.77 Hz, 1 H) 6.91 (d, J=9.09 Hz, 2 H)7.19 (d, J=9.09 Hz, 2 H) 7.54 (d, J=1.77 Hz, 1 H) 10.40 (s, 1 H). [M+H]calc'd for C₂₂H₂₅ClN₄O, 397; found, 397.

Compound 123:(S)-5-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)picolinonitrile

Compound 123 was prepared using a procedure analogous to that describedin connection with compound 1, except that5-(piperazin-1-yl)picolinonitrile was used instead of1-(4-chlorophenyl)piperazine hydrochloride. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.84-2.02 (m, 3 H) 2.09-2.24 (m, 1 H) 2.39-2.48 (m, 4 H) 3.34-3.43(m, 7 H) 3.53-3.64 (m, 1 H) 3.94-4.03 (m, 1 H) 6.97 (d, J=1.77 Hz, 1 H)7.34 (dd, J=8.97, 2.91 Hz, 1 H) 7.61 (d, J=1.52 Hz, 1 H) 7.74 (d, J=8.84Hz, 1 H) 8.40 (d, J=2.78 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd forC₂₁H₂₃N₇O, 390; found, 390.

Compound 124:(S)-N-ethyl-2,5-difluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 124A: tert-butyl4-(4-cyano-2,5-difluorophenyl)piperazine-1-carboxylate: Tert-butylpiperazine-1-carboxylate (0.931 g, 5 mmol) and2,4,6-trifluorobenzonitrile (0.785 g, 5.00 mmol) were combined,potassium carbonate (0.898 g, 6.50 mmol) was added and the reactionmixture was stirred at 90° C. for 1 d. The mixture was triturated withethyl acetate (3×5 mL) and the combined organic extracts were filtered.This was concentrated down to about 5-10 mL and subjected to flashcolumn chromatography on silica gel (120 g SiO₂, hexanes:ethyl acetate1:0 to 4:1) to afford tert-butyl4-(4-cyano-2,5-difluorophenyl)piperazine-1-carboxylate (1.363 g, 4.22mmol, 84% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.41(s, 9 H) 3.12-3.27 (m, 4 H) 3.45 (d, J=4.80 Hz, 4 H) 7.12 (dd, J=11.87,7.07 Hz, 1 H) 7.80 (dd, J=12.88, 6.32 Hz, 1 H).

Compound 124B:4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,5-difluorobenzoic acid:Tert-butyl 4-(4-cyano-2,5-difluorophenyl)piperazine-1-carboxylate (20mg, 0.062 mmol) was dissolved in ethanol (1 mL) and treated with water(0.2 mL) and 50% NaOH (0.2 mL, 2.500 mmol). The reaction mixture wasstirred at 90° C. for 1 h, diluted with water (2 mL) and acidified with1N HCl to pH<4. The solid was filtered, washed with water and dried invacuum to afford4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,5-difluorobenzoic acid (21.0mg, 0.061 mmol, 99% yield) as a white solid. ESI-MS: m/z 343 (M+H)⁺.

Compound 124C: tert-butyl4-(4-(ethylcarbamoyl)-2,5-difluorophenyl)piperazine-1-carboxylate:4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,5-difluorobenzoic acid(0.021 g, 0.061 mmol) and ethylamine hydrochloride (7.50 mg, 0.092 mmol)were suspended in DMF (Volume: 0.7 mL) and treated with DIPEA (0.054 mL,0.307 mmol) and2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (0.047 g, 0.123 mmol). The reaction mixture wasstirred at room temperature for 15 min and diluted with water. Theprecipitate was filtered, washed with water and dried in vacuum toafford tert-butyl4-(4-(ethylcarbamoyl)-2,5-difluorophenyl)piperazine-1-carboxylate (20.1mg, 0.054 mmol, 89% yield). ESI-MS: m/z 370 (M+H)⁺.

Compound 124D: N-ethyl-2,5-difluoro-4-(piperazin-1-yl)benzamide:tert-butyl4-(4-(ethylcarbamoyl)-2,5-difluorophenyl)piperazine-1-carboxylate (0.020g, 0.054 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirredfor 30 min. The thick white precipitate that formed was diluted withethyl ether (10 mL) and stirred until a fine suspension resulted. Theprecipitate was filtered under nitrogen and dried in vacuum to affordN-ethyl-2,5-difluoro-4-(piperazin-1-yl)benzamide hydrochloride (16.2 mg,0.053 mmol, 98% yield) as a white solid. ESI-MS: m/z 270 (M+H)⁺.

Compound 124:(S)-N-ethyl-2,5-difluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(10.76 mg, 0.049 mmol), N-ethyl-2,5-difluoro-4-(piperazin-1-yl)benzamidehydrochloride (15 mg, 0.049 mmol), (cyanomethyl)trimethylphosphoniumiodide (17.88 mg, 0.074 mmol) and N,N-diisopropylethylamine (0.043 mL,0.245 mmol) were suspended in propiononitrile (Volume: 0.2 mL) andheated in a closed vial at 90° C. for 2 h. The reaction mixture became adark brown solution. It was cooled to room temperature, diluted withdichloromethane (2 mL) and methanol (0.3 mL), and purified using flashcolumn chromatography on silica gel (12 g SiO₂, dichloromethane-methanol100:0-90:10). The resulting solid was suspended in ether (1 mL), stirreduntil a fine suspension resulted, filtered and the solid wasrecrystallized from MeOH-water (1:7, 4 mL) and dried in vacuum to afford(S)-N-ethyl-2,5-difluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(8.5 mg, 0.018 mmol, 36.8% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.02 (t, J=7.20 Hz, 3 H) 1.76-1.97 (m, 3 H) 2.11 (m,J=6.44, 4.17 Hz, 1 H) 2.36-2.42 (m, 4 H) 3.03 (br. s., 4 H) 3.12-3.22(m, 2 H) 3.28-3.37 (m, 3 H) 3.46-3.59 (m, 1 H) 3.86-3.97 (m, 1 H) 6.81(dd, J=12.63, 7.07 Hz, 1 H) 6.91 (d, J=1.77 Hz, 1 H) 7.30 (dd, J=13.64,6.82 Hz, 1 H) 7.55 (d, J=1.52 Hz, 1 H) 7.95-8.04 (m, 1 H) 10.38 (s, 1H). [M+H] calc'd for C₂₄H₂₈F₂N₆O₂, 471; found, 471.

Compound 125:(S)-N-ethyl-2-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(76 mg, 0.348 mmol), N-ethyl-2-fluoro-4-(piperazin-1-yl)benzamidehydrochloride (100 mg, 0.348 mmol), (cyanomethyl)trimethylphosphoniumiodide (127 mg, 0.521 mmol) and N,N-diisopropylethylamine (0.303 ml,1.738 mmol) were suspended in propiononitrile (Volume: 1.370 ml) andheated in a closed vial at 120° C. for 3 h. The reaction mixture becamea dark brown suspension. It was cooled to room temperature, concentratedin vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic,10-95% ACN in water). The fractions were concentrated in vacuo and theresulting solid was recrystallized from water-methanol (5:1, 6 mL) anddried in vacuum to afford(S)-N-ethyl-2-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(28.5 mg, 0.063 mmol, 18.12% yield) as a brownish solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 1.13 (t, J=7.20 Hz, 3 H) 1.83-2.02 (m, 3 H) 2.18(dd, J=6.44, 4.17 Hz, 1 H) 2.44-2.49 (m, 4 H) 2.81-3.01 (m, 4 H)3.23-3.32 (m, 2 H) 3.34-3.44 (m, 3 H) 3.52-3.64 (m, 1 H) 3.93-4.01 (m, 1H) 6.91 (td, J=8.21, 2.53 Hz, 1 H) 6.97 (d, J=1.77 Hz, 1 H) 7.00 (dd,J=11.37, 2.53 Hz, 1 H) 7.62 (d, J=1.52 Hz, 1 H) 7.67 (dd, J=8.46, 7.20Hz, 1 H) 8.86 (t, J=5.43 Hz, 1 H) 10.45 (s, 1 H). [M+H] calc'd forC₂₄H₂₉FN₆O₂, 453; found, 453.

Compound 126:(S)-N-ethyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 126A: 3,4-difluoro-N-ethylbenzamide: Using ethanaminehydrochloride and 3,4-difluorobenzoic acid in the general procedure forcoupling of amines to carboxylic acids, the title compound was obtained(56% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12(t, J=7.20 Hz, 3 H) 3.28 (qd, J=7.24, 5.56 Hz, 2 H) 7.55 (dt, J=10.48,8.40 Hz, 1 H) 7.73 (m, J=7.33, 4.74, 2.08, 1.14, 1.14 Hz, 1 H) 7.88(ddd, J=11.75, 7.83, 2.15 Hz, 1 H) 8.58 (t, J=4.93 Hz, 1 H). ESI-MS: m/z186.1 (M+H)⁺. mp=94.1-96.2° C.

Compound 126B: 3-fluoro-N-ethyl-4-(piperazin-1-yl)benzamide: Using3,4-difluoro-N-ethylbenzamide in the general procedure for nucleophilicaromatic substitution reactions, the title compound was obtained (80%yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10 (t, J=7.20Hz, 3 H) 2.31 (br. s., 1 H) 2.79-2.87 (m, 4 H) 2.95-3.03 (m, 4 H) 3.26(qd, J=7.20, 5.68 Hz, 2 H) 7.03 (t, J=8.59 Hz, 1 H) 7.55-7.65 (m, 2 H)8.35 (t, J=5.43 Hz, 1 H). ESI-MS: m/z 252.2 (M+H)⁺. mp=142.4-144.9° C.

Compound 126:(S)-N-ethyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(126):(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), N-ethyl-3-fluoro-4-(piperazin-1-yl)benzamidehydrochloride (131 mg, 0.456 mmol), (cyanomethyl)trimethylphosphoniumiodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml,2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) andheated in a closed vial at 90° C. for 4 h. The reaction mixture became adark brown solution. It was cooled to room temperature, concentrated invacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95%ACN in water). The fractions were concentrated in vacuo and theresulting solid was recrystallized from water-methanol (5:1, 6 mL) anddried in vacuum to afford(S)-N-ethyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(82.3 mg, 0.182 mmol, 39.9% yield) as a yellow-green solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 0.98-1.08 (m, 3 H) 1.77-1.96 (m, 3 H) 2.04-2.18 (m,1 H) 2.35-2.43 (m, 4 H) 2.93-3.07 (m, 4 H) 3.13-3.23 (m, 2 H) 3.28-3.38(m, 3 H) 3.47-3.57 (m, 1 H) 3.88-3.95 (m, 1 H) 6.92 (d, J=2.02 Hz, 1 H)6.97 (t, J=8.84 Hz, 1 H) 7.47-7.57 (m, 3 H) 8.28 (t, J=5.56 Hz, 1 H)10.37 (s, 1 H). [M+H] calc'd for C₂₄H₂₉FN₆O₂, 453; found, 453.

Compound 127:(S)-3-chloro-N-ethyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamidehydrochloride (139 mg, 0.456 mmol), (cyanomethyl)trimethylphosphoniumiodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml,2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) andheated in a closed vial at 90-120° C. for 4 h. The reaction mixturebecame a dark brown solution. It was cooled to room temperature,concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC(basic, 10-95% ACN in water). The fractions were concentrated in vacuoand the resulting solid was recrystallized from water-methanol (5:1, 6mL) and dried in vacuum to afford(S)-3-chloro-N-ethyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(75.6 mg, 0.161 mmol, 35.3% yield) as a tan solid. ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.03 (t, J=7.20 Hz, 3 H) 1.76-1.93 (m, 3 H) 2.06-2.17 (m,1 H) 2.44-2.51 (m, 4 H) 2.96 (br. s., 4 H) 3.14-3.23 (m, 2 H) 3.28-3.38(m, 3 H) 3.46-3.58 (m, 1 H) 3.88-3.97 (m, 1 H) 6.92 (d, J=2.02 Hz, 1 H)7.10 (d, J=8.34 Hz, 1 H) 7.56 (d, J=1.77 Hz, 1 H) 7.70 (dd, J=8.34, 2.02Hz, 1 H) 7.81 (d, J=2.27 Hz, 1 H) 8.37 (t, J=5.43 Hz, 1 H) 10.38 (s, 1H). [M+H] calc'd for C₂₄H₂₉ClN₆O₂, 469; found, 469.

Compound 128:(S)-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide

Compound 128A: N-methyl-4-(piperazin-1-yl)benzenesulfonamide:4-fluoro-N-methylbenzenesulfonamide (189 mg, 0.999 mmol) and piperazine(430 mg, 4.99 mmol) were combined and the reaction mixture was stirredat 120° C. for 2 h. It was diluted with water (5 mL) and stirred until afine suspension resulted. The precipitate was filtered, washed withwater (5×3 mL) and dried in vacuum to affordN-methyl-4-(piperazin-1-yl)benzenesulfonamide (222 mg, 0.869 mmol, 87%yield) as a white solid. ESI-MS: m/z 256 (M+H)⁺.

Compound 128:(S)-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), N-methyl-4-(piperazin-1-yl)benzenesulfonamide (116mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) weresuspended in propiononitrile (Volume: 1.370 ml) and heated in a closedvial at 90-120° C. for 4 h. The reaction mixture became a dark brownsolution. It was cooled to room temperature, concentrated in vacuo,dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN inwater). The fractions were concentrated in vacuo and the resulting solidwas recrystallized from water-methanol (2:1, 6 mL) and dried in vacuumto afford(S)-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzenesulfonamide(110 mg, 0.241 mmol, 52.8% yield) as a tan solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.88-2.04 (m, 3 H) 2.15-2.27 (m, 1 H) 2.38 (d, J=4.80 Hz,3 H) 2.51 (d, J=4.29 Hz, 4 H) 3.32 (br. s., 4 H) 3.38-3.49 (m, 3 H)3.57-3.69 (m, 1 H) 3.97-4.07 (m, 1 H) 7.02 (d, J=1.52 Hz, 1 H) 7.07 (d,J=9.09 Hz, 2 H) 7.15 (q, J=4.72 Hz, 1 H) 7.59 (d, J=8.84 Hz, 2 H) 7.66(d, J=1.77 Hz, 1 H) 10.48 (s, 1 H). [M+H] calc'd for C₂₄H₂₉ClN₆O₂, 457;found, 457.

Compound 129:(S)-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), 3-methyl-4-(piperazin-1-yl)benzonitrile (92 mg,0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) weresuspended in propiononitrile (Volume: 1.370 ml) and heated in a closedvial at 90-120° C. for 4 h. The reaction mixture became a dark brownsolution. It was cooled to room temperature, concentrated in vacuo,dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN inwater). The fractions were concentrated in vacuo and the resulting solidwas recrystallized from water (6 mL) and dried in vacuum to afford(S)-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile(90.1 mg, 0.224 mmol, 49.1% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 1.85-2.01 (m, 3 H) 2.12-2.21 (m, 1 H) 2.24 (s, 3 H)2.43-2.55 (m, 4 H) 2.85-2.97 (m, 4 H) 3.35-3.44 (m, 3 H) 3.53-3.63 (m, 1H) 3.95-4.03 (m, 1 H) 6.98 (d, J=2.02 Hz, 1 H) 7.05-7.12 (m, 1 H)7.54-7.60 (m, 2 H) 7.62 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'dfor C₂₃H₂₆N₆O, 403; found, 403.

Compound 130:(S)-3-((4-(4-fluoro-2-methylphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

Compound 130A: 1-(4-fluoro-2-methylphenyl)piperazine:Bis(2-chloroethyl)amine hydrochloride (1.79 g, 10.03 mmol) and4-fluoro-2-methylaniline (1.26 g, 10.07 mmol) were dissolved in2-propanol (Volume: 10 mL) and stirred in a closed vial at 100° C.overnight. The reaction mixture was diluted with i-PrOH (10 mL) andcooled to 10° C. The resulting precipitate was filtered and purifiedusing HPLC (10-80% ACN in water, TFA-buffered). The fractions wereconcentrated in vacuo, suspended in ether (3 mL) and treated with 4N HClin dioxane (1 mL). The precipitate was filtered and dried in vacuum toafford 1-(4-fluoro-2-methylphenyl)piperazine dihydrochloride (150 mg,0.561 mmol, 5.60% yield). ESI-MS: m/z 195 (M+H)⁺.

Compound 130:(S)-3-((4-(4-fluoro-2-methylphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), 1-(4-fluoro-2-methylphenyl)piperazinedihydrochloride (122 mg, 0.456 mmol), (cyanomethyl)trimethylphosphoniumiodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml,2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) andheated in a closed vial at 90-120° C. for 4 h. The reaction mixturebecame a dark brown solution. It was cooled to room temperature,concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC(basic, 45-95% ACN in water, basic). The fractions were concentrated invacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6mL) and dried in vacuum to afford(S)-3-((4-(4-fluoro-2-methylphenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(102.3 mg, 0.259 mmol, 56.7% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.80-2.02 (m, 3 H) 2.09-2.20 (m, 1 H) 2.23 (s, 3 H)2.37-2.49 (m, 4 H) 2.77 (br. s., 4 H) 3.34-3.44 (m, 3 H) 3.52-3.65 (m, 1H) 3.93-4.03 (m, 1 H) 6.88-7.07 (m, 4 H) 7.62 (s, 1 H) 10.44 (s, 1 H).[M+H] calc'd for C₂₂H₂₆FN₅O, 396; found, 396.

Compound 131:(S)-3-fluoro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamidehydrochloride (125 mg, 0.456 mmol), (cyanomethyl)trimethylphosphoniumiodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml,2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) andheated in a closed vial at 90-120° C. for 4 h. The reaction mixturebecame a dark brown solution. It was cooled to room temperature,concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC(basic, 45-95% ACN in water, basic). The fractions were concentrated invacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6mL) and dried in vacuum to afford(S)-3-fluoro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(128.5 mg, 0.293 mmol, 64.2% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.83-2.03 (m, 3 H) 2.09-2.25 (m, 1 H) 2.50 (m, 4 H)2.75 (d, J=4.29 Hz, 3 H) 2.96-3.14 (m, 4 H) 3.35-3.45 (m, 3 H) 3.53-3.65(m, 1 H) 3.93-4.05 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.04 (t, J=8.59 Hz,1 H) 7.51-7.67 (m, 3 H) 8.27-8.38 (m, 1 H) 10.44 (s, 1 H). [M+H] calc'dfor C₂₃H₂₇FN₆O₂, 439; found, 439.

Compound 132:(S)-N-cyclopropyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), N-cyclopropyl-3-fluoro-4-(piperazin-1-yl)benzamidehydrochloride (137 mg, 0.456 mmol), (cyanomethyl)trimethylphosphoniumiodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml,2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) andheated in a closed vial at 90-120° C. for 4 h. The reaction mixturebecame a dark brown solution. It was cooled to room temperature,concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC(basic, 45-95% ACN in water, basic). The fractions were concentrated invacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6mL) and dried in vacuum to afford(S)-N-cyclopropyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(85.3 mg, 0.184 mmol, 40.3% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.45-0.61 (m, 2 H) 0.61-0.76 (m, 2 H) 1.83-2.05 (m,3 H) 2.08-2.25 (m, 1 H) 2.44-2.49 (m, 4 H) 2.80 (td, J=7.33, 3.79 Hz, 1H) 3.08 (br. s., 4 H) 3.54-3.66 (m, 1 H) 3.91-4.06 (m, 1 H) 6.98 (d,J=1.77 Hz, 1 H) 7.02 (t, J=8.84 Hz, 1 H) 7.49-7.69 (m, 3 H) 8.31 (d,J=4.04 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C₂₅H₂₉FN₆O₂, 465;found, 465.

Compound 133:(S)-3-fluoro-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 133A: tert-butyl4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate:Potassium carbonate (5.56 g, 40.3 mmol) and tert-butylpiperazine-1-carboxylate (6.92 g, 37.2 mmol) were combined, methyl3,4-difluorobenzoate (5.33 g, 31.0 mmol) was added and the reactionmixture was stirred at 90° C. for 1 d. The mixture was triturated withethyl acetate (3×5 mL) and the combined organic extracts were filtered.This was concentrated down to about 5-10 mL and subjected to flashcolumn chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate1:0 to 4:1) to afford tert-butyl4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (4.702 g,13.90 mmol, 44.9% yield) as a white solid. ESI-MS: m/z 339 (M+H)⁺.

Compound 133B: 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoicacid: Tert-butyl4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (4.6 g,13.59 mmol) was suspended in 1,4-Dioxane (Volume: 68.0 ml) and treatedwith 1N LiOH (68.0 ml, 68.0 mmol). The reaction mixture was stirred atroom temperature for 23 h. The reaction mixture was concentrated invacuo until most of the dioxane was gone and acidified with HCl (4.5 N)until a thick precipitate resulted. It was filtered off, washed withwater and dried in vacuum to afford4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (4.40 g,13.57 mmol, 100% yield) as a brown solid. ESI-MS: m/z 325 (M+H)⁺.

Compound 133C: tert-butyl4-(2-fluoro-4-(isopropylcarbamoyl)phenyl)piperazine-1-carboxylate:4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid (1.1 g,3.39 mmol), propan-2-amine (0.241 g, 4.07 mmol),N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.975 g, 5.09 mmol) and 1H-benzo[d][1,2,3]triazol-1-olhydrate (0.779 g, 5.09 mmol) were suspended in DMF (Volume: 13.57 ml)and 4-methylmorpholine (1.864 ml, 16.96 mmol) was added. The reactionmixture was stirred at ambient temperature for 2 h. It was diluted withwater (50 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganic extracts were washed with brine (3×50 mL), dried (MgSO4) andconcentrated in vacuo to afford tert-butyl4-(2-fluoro-4-(isopropylcarbamoyl)phenyl)piperazine-1-carboxylate (1.11g, 3.04 mmol, 89% yield) as an off-white solid. ESI-MS: m/z 366 (M+H)⁺.

Compound 133D: 3-fluoro-N-isopropyl-4-(piperazin-1-yl)benzamide (133D):Tert-butyl4-(2-fluoro-4-(isopropylcarbamoyl)phenyl)piperazine-1-carboxylate (1.10g, 3.01 mmol) was diluted with 4.0M HCl in dioxane (3 mL) and stirredfor 30 min. The thick white precipitate that formed was diluted withethyl ether (10 mL) and stirred until a fine suspension resulted. Theprecipitate was filtered under nitrogen and dried in vacuum to afford3-fluoro-N-isopropyl-4-(piperazin-1-yl)benzamide hydrochloride as awhite solid. ESI-MS: m/z 302 (M+H)⁺.

Compound 133:(S)-3-fluoro-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), 3-fluoro-N-isopropyl-4-(piperazin-1-yl)benzamidehydrochloride (138 mg, 0.456 mmol), (cyanomethyl)trimethylphosphoniumiodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml,2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) andheated in a closed vial at 90-120° C. for 4 h. The reaction mixturebecame a dark brown solution. It was cooled to room temperature,concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC(basic, 45-95% ACN in water, basic). The fractions were concentrated invacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6mL) and dried in vacuum to afford(S)-3-fluoro-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(71.4 mg, 0.153 mmol, 33.6% yield) as a light yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.57 Hz, 6 H) 1.82-2.01 (m, 3 H)2.12-2.24 (m, 1 H) 2.46-2.50 (m, 4 H) 2.98-3.15 (m, 4 H) 3.35-3.44 (m, 3H) 3.54-3.64 (m, 1 H) 3.92-4.14 (m, 2 H) 6.98 (d, J=1.77 Hz, 1 H) 7.03(t, J=8.84 Hz, 1 H) 7.56-7.66 (m, 3 H) 8.09 (d, J=7.83 Hz, 1 H) 10.45(s, 1 H). [M+H] calc'd for C₂₅H₃₁FN₆O₂, 467; found, 467.

Compound 134:(S)-3-chloro-N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), 3-chloro-N-cyclopropyl-4-(piperazin-1-yl)benzamide(128 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg,0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) weresuspended in propiononitrile (Volume: 1.370 ml) and heated in a closedvial at 90-120° C. for 4 h. The reaction mixture became a dark brownsolution. It was cooled to room temperature, concentrated in vacuo,dissolved in DMSO (2 mL) and purified using HPLC (basic, 25-95% ACN inwater, basic). The fractions were concentrated in vacuo and theresulting solid was recrystallized from water-MeOH (2:1, 15 mL) anddried in vacuum toafford(S)-3-chloro-N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(120.4 mg, 0.250 mmol, 54.9% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.50-0.60 (m, 2 H) 0.61-0.72 (m, 2 H) 1.84-2.01 (m,3 H) 2.12-2.23 (m, 1 H) 2.51-2.57 (m, 4 H) 2.77-2.86 (m, 1 H) 3.02 (br.s., 4 H) 3.35-3.46 (m, 3 H) 3.54-3.64 (m, 1 H) 3.95-4.03 (m, 1 H) 6.98(d, J=1.77 Hz, 1 H) 7.16 (d, J=8.34 Hz, 1 H) 7.63 (d, J=1.77 Hz, 1 H)7.75 (dd, J=8.34, 2.02 Hz, 1 H) 7.85 (d, J=2.02 Hz, 1 H) 8.39 (d, J=4.04Hz, 1 H) 10.45 (s, 1 H). [M+H] calc'd for C₂₅H₂₉ClN₆O₂, 481; found, 481.

Compound 135:(S)-3-chloro-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 135A: 3-chloro-4-fluoro-N-isopropylbenzamide: Usingisopropylamine hydrochloride and 3-chloro-4-fluorobenzoic acid in thegeneral procedure for coupling of amines to carboxylic acids, the titlecompound was obtained (81% yield) as a white solid. ESI-MS: m/z 216(M+H)⁺.

Compound 135B: 3-chloro-N-isopropyl-4-(piperazin-1-yl)benzamide: Using3-chloro-4-fluoro-N-isopropylbenzamide in the general procedure fornucleophilic aromatic substitution reactions, the title compound wasobtained (51% yield) as an off-white solid. ESI-MS: m/z 282.2 (M+H)⁺.

Compound 135:(S)-3-chloro-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), 3-chloro-N-isopropyl-4-(piperazin-1-yl)benzamide(129 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg,0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) weresuspended in propiononitrile (Volume: 1.370 ml) and heated in a closedvial at 90-120° C. for 4 h. The reaction mixture became a dark brownsolution. It was cooled to room temperature, concentrated in vacuo,dissolved in DMSO (2 mL) and purified using HPLC (basic, 25-95% ACN inwater, basic). The fractions were concentrated in vacuo and theresulting solid was recrystallized from water-MeOH (2:1, 15 mL) anddried in vacuum to afford(S)-3-chloro-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(122.1 mg, 0.253 mmol, 55.4% yield) as a light tan solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.57 Hz, 6 H) 1.84-2.03 (m, 3 H)2.12-2.25 (m, 1 H) 2.50-2.59 (m, 4 H) 3.02 (br. s., 4 H) 3.35-3.45 (m, 3H) 3.53-3.64 (m, 1 H) 3.94-4.09 (m, 2 H) 6.98 (d, J=1.52 Hz, 1 H) 7.17(d, J=8.59 Hz, 1 H) 7.63 (d, J=1.77 Hz, 1 H) 7.77 (dd, J=8.34, 2.02 Hz,1 H) 7.89 (d, J=2.02 Hz, 1 H) 8.18 (d, J=7.58 Hz, 1 H) 10.45 (s, 1 H).[M+H] calc'd for C₂₅H₃₁ClN₆O₂, 483; found, 483.

Compound 136:(S)-3-chloro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), 3-chloro-N-methyl-4-(piperazin-1-yl)benzamidehydrochloride (132 mg, 0.456 mmol), (cyanomethyl)trimethylphosphoniumiodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml,2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) andheated in a closed vial at 90-120° C. for 4 h. The reaction mixturebecame a dark brown solution. It was cooled to room temperature,concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC(basic, 45-95% ACN in water, basic). The fractions were concentrated invacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6mL) and dried in vacuum to afford(S)-3-chloro-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(53.1 mg, 0.117 mmol, 25.6% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.83-2.02 (m, 3 H) 2.10-2.24 (m, 1 H) 2.51 (br. s.,4 H) 2.75 (d, J=4.55 Hz, 3 H) 3.03 (br. s., 4 H) 3.36-3.45 (m, 3 H)3.52-3.65 (m, 1 H) 3.93-4.03 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.17 (d,J=8.34 Hz, 1 H) 7.63 (d, J=1.77 Hz, 1 H) 7.75 (dd, J=8.34, 2.02 Hz, 1 H)7.86 (d, J=2.02 Hz, 1 H) 8.41 (q, J=4.13 Hz, 1 H) 10.45 (s, 1 H). [M+H]calc'd for C₂₃H₂₇ClN₆O₂, 455; found, 455.

Compound 137:(S)-N-ethyl-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(100 mg, 0.456 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamidehydrochloride (129 mg, 0.456 mmol), (cyanomethyl)trimethylphosphoniumiodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml,2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) andheated in a closed vial at 90-120° C. for 4 h. The reaction mixturebecame a dark brown solution. It was cooled to room temperature,concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC(basic, 45-95% ACN in water, basic). The fractions were concentrated invacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6mL) and dried in vacuum toafford(S)-N-ethyl-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(128.5 mg, 0.286 mmol, 62.8% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.83-2.03 (m, 3 H) 2.09-2.25 (m, 1 H) 2.50 (m, 4 H)2.75 (d, J=4.29 Hz, 3 H) 2.96-3.14 (m, 4 H) 3.35-3.45 (m, 3 H) 3.53-3.65(m, 1 H) 3.93-4.05 (m, 1 H) 6.98 (d, J=1.77 Hz, 1 H) 7.04 (t, J=8.59 Hz,1 H) 7.51-7.67 (m, 3 H) 8.27-8.38 (m, 1 H) 10.44 (s, 1 H). [M+H] calc'dfor C₂₅H₃₂N₆O₂, 449; found, 449.

Compound 138:(S)-3-((4-(4-(pyrrolidine-1-carbonyl)phenyl)piperazin-1-yl)methyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one

In a 1 dram vial,(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) thenadded pyrrolidine (0.024 mL, 0.295 mmol), HATU (140 mg, 0.368 mmol) andN-methylmorpholine (0.108 mL, 0.982 mmol). The rxn was stirred at RTovernight. The mixture was purified by prep HPLC-MS (acidic mode,15-35%). The pH of the combined fractions was adjusted to pH=8-9 andextracted with EtOAc (3×30 ml), washed with brine, dried with MgSO₄,filtered and concentrated to dryness. The residue was taken up withwater/ACN (1:1), and concentrated in vacuo to provide the title compoundas a fluffy white solid (29 mg, 26% yield). m.p.=121.3° C. ¹H NMR (400MHz, DMSO-d6) δ ppm 1.73-1.87 (m, 4 H) 1.87-2.01 (m, 3 H) 2.14-2.21 (m,1 H) 2.43-2.49 (m, 4 H) 3.15-3.23 (m, 4 H) 3.35 (br. s., 2 H) 3.37-3.49(m, 5 H) 3.54-3.65 (m, 1 H) 3.95-4.04 (m, 1 H) 6.91 (d, J=9.09 Hz, 2 H)6.99 (d, J=2.02 Hz, 1 H) 7.42 (d, J=8.84 Hz, 2 H) 7.62 (d, J=1.77 Hz, 1H) 10.44 (s, 1 H). [M+H] calc'd for C₂₆H₃₂N₆O₂, 461; found, 461.

Compound 139:(S)-N,N-dimethyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

In a 1 dram vial,(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) thenadded dimethylamine hydrochloride (24.02 mg, 0.295 mmol), HATU (140 mg,0.368 mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The reactionwas stirred at RT overnight. The mixture was purified by prep HPLC-MS(acidic mode, 15-35%). The pH of the combined fractions was adjusted topH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried withMgSO₄, filtered and concentrated to dryness. The residue was taken upwith water/ACN (1:1), and concentrated in vacuo to provide the titlecompound as a fluffy white solid (21 mg, 19% yield). m.p.=99.2° C. ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.85-2.04 (m, 3 H) 2.12-2.21 (m, 1 H)2.43-2.49 (m, 4 H) 2.94 (s, 6 H) 3.14-3.23 (m, 4 H) 3.35-3.43 (m, 3 H)3.54-3.64 (m, 1 H) 3.94-4.03 (m, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 6.99 (d,J=1.77 Hz, 1 H) 7.29 (d, J=8.84 Hz, 2 H) 7.62 (d, J=1.52 Hz, 1 H) 10.44(s, 1 H). [M+H] calc'd for C₂₄H₃₀N₆O₂, 435; found, 435.

Compound 140:(S)-N-ethyl-N-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

In a 1 dram vial,(S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) thenadded N-methylethanamine (0.025 mL, 0.295 mmol), HATU (140 mg, 0.368mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The reaction wasstirred at RT overnight. The mixture was purified by prep HPLC-MS(acidic mode, 15-35%). The pH of the combined fractions was adjusted topH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried withMgSO₄, filtered and concentrated to dryness. The residue was taken upwith water/ACN (1:1), and concentrated in vacuo to provide the titlecompound as a fluffy white solid (18 mg, 17% yield). m.p.=91.9° C. ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.07 Hz, 3 H) 1.24 (br. s., 3 H)1.85-2.04 (m, 3 H) 2.13-2.21 (m, 1 H) 2.43-2.48 (m, 3 H) 2.90 (s, 3 H)3.14-3.22 (m, 4 H) 3.34-3.43 (m, 3 H) 3.54-3.64 (m, 1 H) 3.95-4.02 (m, 1H) 6.92 (d, J=8.84 Hz, 2 H) 6.99 (d, J=2.02 Hz, 1 H) 7.25 (d, J=8.59 Hz,2 H) 7.62 (d, J=1.77 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd forC₂₅H₃₂N₆O₂, 449; found, 449.

Compound 141:(S)-N,3-dimethyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(300 mg, 1.368 mmol), [Reactants], (cyanomethyl)trimethylphosphoniumiodide (499 mg, 2.053 mmol) and N,N-diisopropylethylamine (1195 μl, 6.84mmol) were suspended in propiononitrile (Volume: 4109 μl) and heated ina closed vial at 120° C. for 2 h. The reaction mixture became a darkbrown solution. It was cooled to room temperature, concentrated invacuo, dissolved in DMSO (2 mL) and purified using HPLC (NH₄HCO₃buffered, 20-70% ACN in water). The fractions were concentrated in vacuoand the resulting solid was recrystallized from water-MeOH (1:1, 5 mL),and then from ACN (30 mL), and dried in vacuum to afford(S)-N,3-dimethyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(232.7 mg, 0.536 mmol, 39.1% yield) as a light tan solid. ¹H NMR(DMSO-d₆) δ: 10.40 (s, 1H), 8.19 (q, J=4.0 Hz, 1H), 7.57-7.66 (m, 3H),6.95-7.04 (m, 2H), 3.93-4.02 (m, 1H), 3.54-3.64 (m, 1H), 3.38 (s, 3H),2.87 (br. s., 4H), 2.74 (d, J=4.5 Hz, 3H), 2.49-2.55 (m, 4H), 2.25 (s,3H), 2.11-2.22 (m, 1H), 1.80-2.02 (m, 3H). [M+H] calc'd for C₂₄H₃₀N₆O₂,435; found, 435.

Compound 142:(S)-N-cyclopropyl-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

To a suspension of(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(0.1 g, 0.456 mmol), N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamidedihydrochloride (0.179 g, 0.538 mmol), and(cyanomethyl)trimethylphosphonium iodide (0.188 g, 0.775 mmol) inPropiononitrile (Volume: 2.0 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.556 mL, 3.19 mmol) at 23° C. Thereaction was stirred at 90° C. for 8 hr. The reaction mixture was cooledto room temperature, filtered, and rinsed with propiononitrile (3×1 mL).The resulting solid was reconstituted in DMSO (Volume: 3.0 mL) andpurified via preparative mass trigger LCMS using a gradient eluant of25-65% ACN: 10 mM NH₄HCO₃ (aq). The collected fractions were combinedand the ACN was removed via rotary evaporation to furnish a suspension.The suspension was filtered, rinsed with H2O (3×10 mL), and theresulting solid was dried in vacuo to provide(S)-N-cyclopropyl-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)_(b)enzamide (0.0624 g, 0.135 mmol, 29.7% yield) as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.50-0.59 (m, 2 H) 0.60-0.70 (m, 2 H)1.86-2.00 (m, 3 H) 2.14-2.20 (m, 1 H) 2.25 (s, 3 H) 2.47-2.50 (m, 4 H)2.76-2.93 (m, 5 H) 3.34-3.44 (m, 3 H) 3.55-3.63 (m, 1 H) 3.93-4.02 (m, 1H) 6.96-7.04 (m, 2 H) 7.56-7.67 (m, 3 H) 8.22 (d, J=4.29 Hz, 1 H) 10.45(s, 1 H). ESI-MS: m/z 461.4 (M+H)⁺. mp=226.7-233.5° C.

Compound 143:N-ethyl-4-(4-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide

Compound 143A: Methyl6-(2-(methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate: Methyl1H-pyrrole-2-carboxylate (5.78 g, 46.2 mmol) was dissolved in DMSO andcooled to 10° C. NaH was added in two portions over 5 min. The reactionmixture was stirred at 10° C. for 10 min and methyl6-chloro-5-nitronicotinate (5 g, 23.09 mmol) in DMSO (10 mL) was addedslowly over 3 min. The red reaction mixture was allowed to warm to roomtemperature and stirred overnight. It was cooled to 0° C. and quenchedwith water (12 mL) and diluted with brine (50 mL). The mixture waswashed with EtOAc (2×25 mL) and the aqueous layer was acidified to pH=2with 4.5 N HCl. It was extracted with EtOAc (1×100 mL) and the organiclayer was dried (Na₂SO₄), filtered and concentrated in vacuo to afford ayellow solid, which was dissolved in MeOH (100 mL) and cooled to 0° C.Thionyl chloride (45 mL, 617 mmol) was added slowly over 5 min. Thereaction mixture was stirred at 0° C. for 1 h and then at roomtemperature overnight. It was concentrated in vacuo and the resultingsolid was triturated with ethyl acetate (300 mL). The solid was filteredoff and the filtrate was concentrated in vacuo. then washed with ethylether to afford methyl6-(2-(methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (5.04 g, 16.51mmol, 92% yield) as a yellow solid, [M+H] calc'd for C₁₃H₁₁N₃O₆, 306;found, 306.

Compound 143B: Methyl6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate:Methyl 6-(2-(methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (5.00 g,16.38 mmol) was dissolved in dichloromethane (Volume: 82 ml) and to thissolution was added triphenyl phosphite (0.051 g, 0.164 mmol), ammoniummetavanadate (0.115 g, 0.983 mmol) and Pt/C (5% wt.) (0.639 g, 0.164mmol). The reaction mixture was hydrogenated at 100 psi at 25° C. for 36h. The reaction mixture was filtered through a short plug of celite andthe plug and precipitate were washed well with methanol (100 mL) andthen MeOH:DCM (100 mL, 1:1). The solids (celite and Pt/C) werecontinuously extracted with MeOH/DCM mixture (1:1) in a Soxlet extractorfor 2 d. The extracts were combined with the earlier filtrates,concentrated in vacuo, crystallized with MeOH (100 mL) and the resultingsolid was filtered off and suspended in ethyl ether (200 mL). The solidwere filtered off and dried in vacuum to afford methyl6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (2.15g, 8.84 mmol, 54.0% yield) as a grey solid. ¹H NMR (DMSO-d₆) δ 11.49 (s,1H), 8.69 (s, 1H), 8.15 (br. s., 1H), 8.11 (s, 1H), 7.16 (d, J=2.5 Hz,1H), 6.78 (t, J=3.0 Hz, 1H), 3.91 (s, 3H). [M+H] calc'd for C₁₂H₉N₃O₃,244. found, 244.

Compound 143C:3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one: Methyl6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (2.0g, 8.22 mmol) was suspended in THF (Volume: 27.4 ml) under nitrogenatmosphere and cooled to 0° C. Sodium hydride (0.658 g, 16.45 mmol) wasadded in several portions over 7 min. The reaction mixture was stirredat 0° C. for 10 min, at room temperature for 20 min and cooled to below−50° C. Lithium aluminum hydride (7.40 ml, 14.80 mmol) was added overthe period of 5 min and the reaction was kept at a temperature between−30 and −20° C. for 1 h. The mixture was cooled to below −40° C. andMeOH (6 mL) was added. Water (5 mL) was added and then more MeOH (50mL). The reaction mixture was stirred at rt for 10 min. The resultingprecipitate was filtered, suspended in MeOH (100 mL) and filtered again.The solid was suspended with heating overnight in MeOH:DCM (1:1, 200 mL)and filtered hot. This solid was dissolved in MeOH/DCM (100 mL, 3:1) andloaded onto silica gel (12 g) then purified by flash columnchromatography on silica gel (220 g SiO2, gradient DCM:MeOH 100:1-85:15)to give 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one(854 mg, 3.97 mmol, 48.3% yield) as a white solid. ¹H NMR (DMSO-d6) δ11.36 (br. s., 1H), 8.14 (d, J=1.8 Hz, 1H), 8.10 (dd, J=2.8, 1.5 Hz,1H), 7.61-7.66 (m, 1H), 7.09 (dd, J=3.8, 1.5 Hz, 1H), 6.71 (dd, J=3.7,2.9 Hz, 1H), 5.42 (br. s., 1H), 4.53-4.64 (m, 2H). [M+H] calc'd forC₁₁H₉N₃O₂, 216; found, 216.

Compound 143:N-ethyl-4-(4-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide:3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg,0.465 mmol), N-ethyl-4-(piperazin-1-yl)benzamide (119 mg, 0.511 mmol),(cyanomethyl)trimethylphosphonium iodide (158 mg, 0.651 mmol) andN,N-diisopropylethylamine (406 μl, 2.323 mmol) were suspended inpropiononitrile (Volume: 1395 μl) and heated in a small closed vial for7 h at 90-120° C. (the temperature was increased by 10° C. after 4, 5and 6 h. An additional portion of (cyanomethyl)trimethylphosphoniumiodide (43.3 mg) was added after 4 h. The reaction mixture was cooled tort, filtered and the precipitate was washed with MeCN (5 mL) to give anoff-white solid (168.4 mg). The solid was heated to reflux in EtOH (15mL) for 5 min and allowed to cool to ambient temperature. It wasfiltered and dried in vacuum to affordN-ethyl-4-(4-((6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide(112.5 mg, 0.261 mmol, 56.2% yield) as a while solid. ¹H NMR (DMSO-d₆)δ: 11.31 (s, 1H), 8.08-8.17 (m, 3H), 7.71 (d, J=8.8 Hz, 2H), 7.66 (d,J=1.8 Hz, 1H), 7.09 (dd, J=3.7, 1.6 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H),6.72 (dd, J=3.7, 2.9 Hz, 1H), 3.62 (s, 2H), 3.20-3.28 (m, 6H), 2.52-2.59(m, 4H), 1.09 (t, J=7.2 Hz, 3H). [M+H] calc'd for C₂₄H₂₆N₆O₂, 431;found, 431.

Compound 144:(S)-3-((4-(4-(2-methoxypyridin-4-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 144A:(S)-3-((4-(4-bromophenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one:Compound 144 was prepared using a procedure analogous to that describedin connection with compound 68, except that 1-(4-bromophenyl)piperazinewas used instead of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridinehydrochloride to give a white solid: [M+H] calc'd for C₂₂H₂₆BrN₅O, 456;found, 456.

Compound 144:(S)-3-((4-(4-(2-methoxypyridin-4-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one:(S)-3-((4-(4-bromophenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one(0.04 mmol), 2-methoxypyridin-4-ylboronic acid (0.060 mmol),PdCl2(dppf)-CH₂Cl₂ Adduct (3.27 mg, 4.00 μmol), sodium bicarbonate(0.500 ml, 0.500 mmol), dioxane (Volume: 1 ml) and a stir bar weresealed in a 5 mL microwave vial. The vial was heated to 135° C. for 30minutes. The aqueous layer was removed from the vial and reactionmixture the filtered into a 1.8 mL HPLC submission vial. The reactionmixture was purified by LCMS to give a yellow solid: [M+H] calc'd forC₂₈H₃₂N₆O₂, 485; found, 485.

Compound 145:(S)-3-((4-(4-(6-aminopyridin-2-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 145 was prepared using a procedure analogous to that describedin connection with compound 144, except that6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine was usedinstead of 2-methoxypyridin-4-ylboronic acid to give a white solid asthe TFA salt after purification by HPLC-MS: [M+H] calc'd for C₂₇H₃₁N₇O,470; found, 470.

Compound 146:(S)-3-((4-(4-(thiophen-3-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 146 was prepared using a procedure analogous to that describedin connection with compound 144, except that thiophen-3-ylboronic acidwas used instead of 2-methoxypyridin-4-ylboronic acid to give a whitesolid as the TFA salt after purification by HPLC-MS: [M+H] calc'd forC₂₆H₂₉N₅OS, 460; found, 460.

Compound 147:(S)-3-((4-(4-(thiophen-2-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 147 was prepared using a procedure analogous to that describedin connection with compound 144, except that thiophen-2-ylboronic acidwas used instead of 2-methoxypyridin-4-ylboronic acid to give a brownsolid as the TFA salt after purification by HPLC-MS: [M+H] calc'd forC₂₆H₂₉N₅OS, 460; found, 460.

Compound 148:(S)-3-((4-(4-(pyridin-4-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 148 was prepared using a procedure analogous to that describedin connection with compound 144, except that pyridin-4-ylboronic acidwas used instead of 2-methoxypyridin-4-ylboronic acid to give a brownsolid as the TFA salt after purification by HPLC-MS: [M+H] calc'd forC₂₇H₃₀N₆O, 455; found, 455.

Compound 149:(S)-3-((4-(biphenyl-4-yl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 149 was prepared using a procedure analogous to that describedin connection with compound 144, except that phenylboronic acid was usedinstead of 2-methoxypyridin-4-ylboronic acid to give a brown solid asthe TFA salt after purification by HPLC-MS: [M+H] calc'd for C₂₈H₃₁N₅O,454; found, 454.

Compound 150:(S)-3-((4-(4-(6-methoxypyridin-3-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 150 was prepared using a procedure analogous to that describedin connection with compound 144, except that6-methoxypyridin-3-ylboronic acid was used instead of2-methoxypyridin-4-ylboronic acid to give a white solid as the TFA saltafter purification by HPLC-MS: [M+H] calc'd for C₂₈H₃₂N₆O₂, 485; found,485.

Compound 151:(S)-3-((4-(4-(pyrimidin-5-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 151 was prepared using a procedure analogous to that describedin connection with compound 144, except that pyrimidin-5-ylboronic acidwas used instead of 2-methoxypyridin-4-ylboronic acid to give a whitesolid as the TFA salt after purification by HPLC-MS: [M+H] calc'd forC₂₆H₂₉N₇O, 456; found, 456.

Compound 152:(S)-3-((4-(4-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 152 was prepared using a procedure analogous to that describedin connection with compound 144, except that2-methoxypyrimidin-5-ylboronic acid was used instead of2-methoxypyridin-4-ylboronic acid to give a green solid as the TFA saltafter purification by HPLC-MS: [M+H] calc'd for C₂₇H₃₁N₇O₂, 486; found,486.

Compound 153:(S)-3-((4-(4-(3-methoxypyridin-4-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 153 was prepared using a procedure analogous to that describedin connection with compound 144, except that3-methoxypyridin-4-ylboronic acid was used instead of2-methoxypyridin-4-ylboronic acid to give a brown solid as the TFA saltafter purification by HPLC-MS: [M+H] calc'd for C₂₈H₃₂N₆O₂, 485; found,485.

Compound 154:(S)-3-((4-(2′-methylbiphenyl-4-yl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 154 was prepared using a procedure analogous to that describedin connection with compound 144, except that o-tolylboronic acid wasused instead of 2-methoxypyridin-4-ylboronic acid to give a gray solidas the TFA salt after purification by HPLC-MS: [M+H] calc'd forC₂₉H₃₃N₅O, 468; found, 468.

Compound 155:(S)-3-((4-(4-(3-methylpyridin-4-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 155 was prepared using a procedure analogous to that describedin connection with compound 144, except that 3-methylpyridin-4-ylboronicacid was used instead of 2-methoxypyridin-4-ylboronic acid to give abrown solid as the TFA salt after purification by HPLC-MS: [M+H] calc'dfor C₂₈H₃₂N₆O, 469; found, 469.

Compound 156:(S)-3-((4-(4-(6-methoxypyridin-2-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 156 was prepared using a procedure analogous to that describedin connection with compound 144, except that2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine wasused instead of 2-methoxypyridin-4-ylboronic acid to give a brown solidas the TFA salt after purification by HPLC-MS: [M+H] calc'd forC₂₈H₃₂N₆O₂, 485. found, 485.

Compound 157:(S)-3-((4-(4-(pyridin-2-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 157 was prepared using a procedure analogous to that describedin connection with compound 144, except that2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used insteadof 2-methoxypyridin-4-ylboronic acid to give a yellow solid as the TFAsalt after purification by HPLC-MS: [M+H] calc'd for C₂₇H₃₀N₆O, 455;found, 455.

Compound 158:(S)-3-((4-(4-(pyridin-3-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 158 was prepared using a procedure analogous to that describedin connection with compound 144, except that pyridin-3-ylboronic acidwas used instead of 2-methoxypyridin-4-ylboronic acid to give a brownsolid as the TFA salt after purification by HPLC-MS: [M+H] calc'd forC₂₇H₃₀N₆O, 455; found, 455.

Compound 159:(S)-3-((4-(4-(5-methylthiophen-2-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 159 was prepared using a procedure analogous to that describedin connection with compound 144, except that5-methylthiophen-2-ylboronic acid was used instead of2-methoxypyridin-4-ylboronic acid to give a brown solid as the TFA saltafter purification by HPLC-MS: [M+H] calc'd for C₂₇H₃₁N₅OS, 474; found,474.

Compound 160:(S)-3-((4-(2′-(hydroxymethyl)biphenyl-4-yl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 160 was prepared using a procedure analogous to that describedin connection with compound 144, except thatbenzo[c][1,2]oxaborol-1(3H)-ol was used instead of2-methoxypyridin-4-ylboronic acid to give a gray solid as the TFA saltafter purification by HPLC-MS: [M+H] calc'd for C₂₉H₃₃N₅O₂, 484; found,484.

Compound 161:(S)-3-((4-(4-(4-methylthiophen-3-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 161 was prepared using a procedure analogous to that describedin connection with compound 144, except that4-methylthiophen-3-ylboronic acid was used instead of2-methoxypyridin-4-ylboronic acid to give a white solid as the TFA saltafter purification by HPLC-MS: [M+H] calc'd for C₂₇H₃₁N₅OS, 474; found,474.

Compound 162:(S)-3-((4-(4-(3-methylthiophen-2-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 162 was prepared using a procedure analogous to that describedin connection with compound 144, except that3-methylthiophen-2-ylboronic acid was used instead of2-methoxypyridin-4-ylboronic acid to give a yellow solid as the TFA saltafter purification by HPLC-MS: [M+H] calc'd for C₂₇H₃₁N₅OS, 474; found,474.

Compound 163:(S)-3-((4-(4-(5-oxocyclopent-1-enyl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 163 was prepared using a procedure analogous to that describedin connection with compound 144, except that5-oxocyclopent-1-enylboronic acid was used instead of2-methoxypyridin-4-ylboronic acid to give a brown solid as the TFA saltafter purification by HPLC-MS: [M+H] calc'd for C₂₇H₃₁N₅O₂, 458; found,458.

Compound 164:(S)-3-((4-(4-(6-methylpyridin-3-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 164 was prepared using a procedure analogous to that describedin connection with compound 144, except that 6-methylpyridin-3-ylboronicacid was used instead of 2-methoxypyridin-4-ylboronic acid to give ablack solid as the TFA salt after purification by HPLC-MS: [M+H] calc'dfor C₂₈H₃₂N₆O, 469; found, 469.

Compound 165:(S)-3-((4-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dioyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 165 was prepared using a procedure analogous to that describedin connection with compound 144, except that1-methyl-1H-pyrazol-4-ylboronic acid was used instead of2-methoxypyridin-4-ylboronic acid to give a white solid as the TFA saltafter purification by HPLC-MS: [M+H] calc'd for C₂₆H₃₁N₇O, 458; found,458.

Compound 166:(S)-3-((4-(4-(4-methylpyridin-2-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 166 was prepared using a procedure analogous to that describedin connection with compound 144, except that4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine wasused instead of 2-methoxypyridin-4-ylboronic acid to give a brown solidas the TFA salt after purification by HPLC-MS: [M+H] calc'd forC₂₈H₃₂N₆O, 469; found, 469.

Compound 167:(S)-3-((4-(4-(2-methylpyridin-4-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 167 was prepared using a procedure analogous to that describedin connection with compound 144, except that 2-methylpyridin-4-ylboronicacid was used instead of 2-methoxypyridin-4-ylboronic acid to give ayellow solid as the TFA salt after purification by HPLC-MS: [M+H] calc'dfor C₂₈H₃₂N₆O, 469; found, 469.

Compound 168:(S)-3-((4-(4-(pyrazin-2-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 168 was prepared using a procedure analogous to that describedin connection with compound 144, except that pyrazin-2-ylboronic acidwas used instead of 2-methoxypyridin-4-ylboronic acid to give a tansolid as the TFA salt after purification by HPLC-MS: [M+H] calc'd forC₂₆H₂₉N₇O, 456; found, 456.

Compound 169:(S)-3-((4-(4-(2-methoxypyridin-3-yl)phenyl)piperazin-1-yl)methyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one

Compound 169 was prepared using a procedure analogous to that describedin connection with compound 144, except that2-methoxypyridin-3-ylboronic acid was used instead of2-methoxypyridin-4-ylboronic acid to give a green solid as the TFA saltafter purification by HPLC-MS: [M+H] calc'd for C₂₈H₃₂N₆O₂, 485; found,485.

Biological Testing

The activity of compounds as PARP inhibitors may be assayed in vitro, invivo or in a cell line. Provided below are descriptions of an in vitroenzymatic PARP activity assay for activity against PARP and a PARPcellular chemopotentiation assay.

Enzymatic PARP Assay Dissociation Constant (K_(D)) from Surface PlasmonResonance

Enzyme Preparation

The catalytic domain of Human PARP was cloned and prepared as describedin Kinoshita, T.; Nakanishi, I.; Warizaya, M.; Iwashita, A.; Kido, Y.;Hattori, K. and Fujii, T. 2006 FEBS Letters 556, 43-46. Purified enzymewas stored at −80° C. in 25 mM Tris(hydroxymethyl)aminomethane (Tris) pH7.4, 150 mM NaCl, 2 mM dithiothreitol (DTT) at a concentration of 6mg/ml.

Biacore Assays

Biacore affinity assays for test compounds were conducted on a BiacoreT100 (GE Healthcare) as follows. A Series S Sensor Chip CM5 (part numberBR-1006-68, GE Healthcare) was activated for amide coupling with anAmine Coupling Kit (part number BR-1000-50, GE Healthcare) as describedby the manufacturer. The mobile phase buffer consisted of Biacore bufferHBS-P (part number BR-1003-68, GE Healthcare) supplemented with 1% v/vdimethylsulfoxide (DMSO), 0.5 mM Tris(2-carboxyethyl)phosphinehydrochloride (TCEP), and 5 mM MgCl2. Enzyme samples (2 μl/6 mg/ml)stored at −80° C. were diluted to 0.080 mg/ml with 10 mM4-morpholineethanesulfonic acid (MES) pH 6.5 and then mounted on theactivated Biacore CM5 chip at a flow rate of 10 μl/min for 240 seconds.When successfully mounted, a signal of approximately 8,000 reflectiveunits was observed. Test compounds were diluted 9 times 2-fold seriallyin mobile phase buffer (listed above) at 1% v/v DMSO final to generate aconcentration gradient bracketing their anticipated K_(D)s. Biacoremounted PARP was given a 1 minute exposure (association phase) tovarious concentrations of test compounds to observe a steady stateequilibrium or an on rate. The exposure was followed with a dissociationphase of 5 minutes. The association and dissociation phases were at aflow rate of 50 μl/min and a temperature of 25° C.

Biacore Binding Analysis

Rapid equilibrium model: If the test compound binding displayed rapidequilibrium, a plot of steady state response versus concentration wasgenerated and the equation Rmax*[compound]/([compound]+K_(D)) was fit tothe profile. Parameters Rmax (response at saturation) and K_(D) (bindingconstant) were calculated through a nonlinear least squares fitting ofthe equation to the data by use of the Biacore T100 analysis software.

Slow binding model: If the binding of the test compound did not achieveequilibrium within the 1 minute exposure, the association rate constantand the dissociation rate constant for the test compound were calculatedthrough the simultaneous analysis of the family of progress curvesobtained from the concentration gradient experiment. Parameteroptimization was through a nonlinear least squares analysis of theassociation phase Response=Rmax*(1−exp(−(k_(on)[cmpd]+k_(off))*t)) anddissociation phase Response=Rmax*exp(−(k_(on)[cmpd]+k_(off))*t) by useof the Biacore T100 analysis software. The binding constant K_(D) wascalculated from the definition K_(D)=k_(off)/k_(on)

Inhibition Constant (IC₅₀) from PARP ELISA

Inhibition of PARP catalytic activity was determined by use of anELISA-based colorimetric PARP/Apoptosis Assay kit (part number4684-096-K HT, Trevigen). To each histone coated well in the 96-wellplate supplied by the manufacturer (part number 4677-096-P) is added 39μl of PARP buffer (part number 4671-096-02) and 1 μl of test compounddissolved in DMSO (diluted serially 3-fold 11 times). After mixing, 5 μlof 0.1 nM PARP (part number 4684-096-01) is added and the solutionallowed to stand at ambient temperature for 10 minutes. PARP catalysisis initiated with the addition of 5 μl of 100 uM β-nicotinamide adeninedinucleotide (NAD+) (part number 4684-096-02) with activated DNA (partnumber 4671-096-06). After 10 minutes of catalysis the reaction isquenched by solvent aspiration followed by irrigation of the assay wells4 times with phosphate buffered saline (PBS) containing 0.1%t-Octylphenoxypolyethoxyethanol (TRITON® X-100). Mouse Anti-poly ADPribose (PAR) monoclonal antibody, goat antimouse immunoglobulin G(IgG)-horse radish peroxidase (HRP) conjugate and HRP substrate areadded according to the manufacture's specifications to generate acolorimetric signal proportional to PARP catalytic activity. An IC₅₀ forthe test compound is calculated from the equationAbsorbance=(Amax−background)/(1+([cmpd]/IC₅₀)^n)+background fit to the12 point test compound concentration gradient via nonlinear leastsquares.

Potentiation Factor (PF₅₀) Determination from PARP CellularChemopotentiation Assay

Jurkat cell line was maintained according to the supplier (American TypeCulture Collection (Rockville, Md.)). Cells were seeded in 96-welltissue culture microplates at 10,000 cells per well and cultured for 24hours prior to addition of compounds, TMZ (Temozolomide) or DMSO(dimethylsulfoxide) vehicle. After 96 hours of treatment, the conversionof MTS([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt], Promega, Madison, Wis.) by metabolically active cells wasdetermined through measuring the OD_(490 nm) with a Spectramaxmicroplate reader (Molecular Devices, San Diego, Calif.). To generateconcentration-response curves, cells were treated in duplicate with arange of serial compound dilutions (final DMSO concentration was 0.5%)in the absence or presence of 100 μM TMZ chemoreagent. The percentage ofviable cells per well was calculated by correction for background andnormalizing against DMSO-treated cells. EC₅₀ values for inhibition ofcell viability were calculated using XLfit4 MicroSoft Excelcurve-fitting software. Chemopotentiation factor PF₅₀ was calculated asthe ratio of EC₅₀ values of cells co-treated without and with TMZ,respectively.

It should be noted that a variety of other expression systems and hostsare also suitable for the expression of PARP, as would be readilyappreciated by one of skill in the art.

TABLE 1 lists pK_(D), pIC₅₀ and PF₅₀ values for select compounds of thepresent invention. Here, pIC₅₀=−log(IC₅₀) and pK_(D)=−log(K_(D)) whereIC₅₀ and K_(D) are expressed in molar concentration.

TABLE 1 pK_(D), pIC₅₀ and PF₅₀ Values of Exemplified Compounds AgainstPARP COMPOUND pK_(D) pIC₅₀ PF₅₀  1 >500  2 >7.5 >2000  3 6.1-7.5 >10  47.4-7.8 >2000  5 >7.5 7.4-7.8 >5000  6A ≧0  6 ≧7.9 >10  7 >10  8 >10  9≧0  10 >7.5 ≧7.9 >5000  11 7.4-7.8 >10  12 7.4-7.8 >10  13 7.4-7.8 >5000 14 >500  15 >500  16 >500  17 >2000  18 >10  19 ≧0  20 ≧0  21 >2000 22 >10  23 ≧0  24 7.4-7.8 >5000  25 ≧0  26 >10  28 ≧0  29 ≦7.3 >500  31≧0  32 ≧0  34 ≧0  35 ≧0  36 ≧0  37 ≦7.3 >2000  38 ≧0  39 ≧0  40 >10  41≧0  42 ≦7.3 >500  45 7.4-7.8 >10  46 ≧0  47 ≦7.3 >10  48 ≧0  49 ≧0  50≧0  51 ≧0  52 >7.5 ≧0  53 6.1-7.5 ≦7.3 ≧0  54 ≦6     56 >7.5 ≧0  57 >7.5≧0  58 ≦6     59 >7.5 ≧0  60 ≦6     61 ≦6     63 6.1-7.5 ≧0  64 >7.5 ≧0 65 ≦6    ≧7.9 >10  66 ≦6    7.4-7.8 >10  67 >7.5 7.4-7.8 ≧0  68≧7.9 >5000  69 ≧7.9 >10  70 ≦7.3 ≧0  71 ≧7.9 >500  72 ≧7.9 >500  73≧7.9 >2000  74 ≧7.9 >10  75 7.4-7.8 >500  76 ≧0  77 7.4-7.8 >10  78 >10 79 >10  80 >7.5 ≦7.3 ≧0  81 6.1-7.5 ≦7.3 ≧0  82 6.1-7.5 ≦7.3 ≧0  83≦6    7.4-7.8 ≧0  84 6.1-7.5 ≧7.9 ≧0  85 6.1-7.5 7.4-7.8 ≧0  86 >7.57.4-7.8 >500  87 7.4-7.8 >10  88 >7.5 ≧7.9 ≧0  89 >10  90 ≧7.9 >10 91 >2000  92 >5000  93 ≧0  94 ≦7.3 ≧0  95 ≦7.3 ≧0  96 ≦7.3  97 ≧0 98 >5000  99 >5000 100 >10 101 ≦7.3 >10 102 7.4-7.8 ≧0 103 7.4-7.8 ≧0104 ≦7.3 ≧0 105 7.4-7.8 >10 106 ≧7.9 >5000 107 7.4-7.8 >2000 108≧7.9 >500 109 7.4-7.8 >2000 110 7.4-7.8 >5000 111 7.4-7.8 >5000 112≧7.9 >10 113 ≦7.3 >2000 114 ≦7.3 >2000 115 7.4-7.8 >2000 116 ≧7.9 >5000117 7.4-7.8 >5000 118 ≧7.9 >5000 120 ≦7.3 ≧0 121 7.4-7.8 ≧0 122 ≦7.3 ≧0123 7.4-7.8 >10 124 ≦7.3 ≧0 125 ≦7.3 ≧0 126 7.4-7.8 >5000 1277.4-7.8 >500 128 ≦7.3 ≧0 129 7.4-7.8 >500 130 7.4-7.8 >2000 131≧7.9 >500 132 ≧7.9 >2000 133 7.4-7.8 >2000 134 7.4-7.8 >5000 1357.4-7.8 >5000 136 ≧7.9 >5000 137 ≧7.9 >5000 138 ≦7.3 ≧0 139 ≦7.3 ≧0 140≦7.3 ≧0 141 ≧7.9 >500 142 ≧7.9 >2000 144 ≦7.3 145 ≦7.3 146 7.4-7.8 147≦7.3 148 7.4-7.8 149 ≦7.3 150 ≦7.3 151 ≦7.3 152 7.4-7.8 153 ≦7.3 154≦7.3 155 ≦7.3 156 ≦7.3 157 ≦7.3 158 ≦7.3 159 ≦7.3 160 ≦7.3 161 ≦7.3 162≦7.3 163 ≦7.3 164 7.4-7.8 165 7.4-7.8 166 7.4-7.8 167 7.4-7.8 1687.4-7.8 169 ≦7.3

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compounds, compositions,kits, and methods of the present invention without departing from thespirit or scope of the invention. Thus, it is intended that the presentinvention cover the modifications and variations of this inventionprovided they come within the scope of the appended claims and theirequivalents.

What is claimed is:
 1. A compound of the formula:

or a tautomer thereof or a pharmaceutically acceptable salt of thecompound or tautomer, wherein X is selected from the group consisting ofO, S and NR₈; R₁ is -L₁-R₁₃; L₁ is —(CR₁₄R₁₅)_(r)—; R₂ is selected fromthe group consisting of hydrogen, halo, nitro, cyano, hydroxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, amino, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,(C₁₋₁₀)oxoalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl; R₆ is selected from thegroup consisting of hydrogen, amino, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl; R₇ is selected from thegroup consisting of hydrogen, halo, nitro, cyano, hydroxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, amino, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,(C₁₋₁₀)oxoalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl; R₈ is selected from thegroup consisting of hydrogen, hydroxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, amino, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl; each R₁₂ isindependently selected from the group consisting of hydrogen, halo,nitro, cyano, hydroxy, (C₄₋₁₂ )aryloxy, hetero(C₁₋₁₀)aryloxy, amino,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,(C₁₋₁₀)oxaalkyl, (C₁₋₁₀)oxoalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₄₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl; R₁₃ is selected fromthe group consisting of

each R₁₄ and R₁₅ is independently selected from the group consisting ofhydrogen, halo, and (C₁₋₃)alkyl; R₁₉ and R₂₀ are each independentlyselected from the group consisting of hydrogen and (C₁₋₃)alkyloptionally substituted with one or more substituents independentlyselected from halo, nitro, cyanohydroxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, amino, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl; R₂₁ and R₂₂ are each independently selectedfrom the group consisting of (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl,wherein the (C₄₋₁₂)aryl and hetero(C₁₋₁₀)aryl substituents are eachoptionally substituted with one or more substituents independentlyselected from halo, nitro, cyano, amino, hydroxy, (C₁₋₁₀)alkoxy,carbonyl, sulfonyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,(C₁₋₁₀)azaalkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl; the optional carbonyl substituent issubstituted with hydrogen, hydroxy, (C₁₋₁₀)alkoxy, (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₁₋₁₂)cycloalkyl, (C₁₋₁₀)alkylamino or aminooptionally substituted with (C₃₋₁₂)cycloalkyl; the optional sulfonylsubstituent is substituted with (C₁₋₁₀)alkyl or (C₁₋₁₀)alkylamino; theoptional (C₃₋₁₂)cycloalkyl and hetero(C₃₋₁₂)cycloalkyl substituents areeach optionally substituted with one or more substituents independentlyselected from cyano, oxo, hydroxy, (C₁₋₁₀)alkoxy, amino, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, andhetero(C₃₋₁₂)cycloalkyl; and the optional (C₄₋₁₂)aryl andhetero(C₁₋₁₀)aryl substituents are each optionally substituted with oneor more substituents independently selected from halo, nitro, cyano,amino, hydroxy, (C₁₋₁₀)alkoxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, and (C₁₋₁₀)azaalkyl; each R₂₈ is independentlyselected from the group consisting of hydrogen, halo, (C₁₋₃)alkyl,(C₁₋₃)alkoxy, amino, and thio; q is selected from the group consistingof 0, 1, 2, 3, 4, 5 and 6; r is selected from the group consisting of 1,2 and 3; s is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6,7 and 8; and Y is selected from the group consisting of O and S.
 2. Thecompound, tautomer or pharmaceutically acceptable salt according toclaim 1, wherein each R₁₂ is independently selected from the groupconsisting of hydrogen, halo, and (C₁₋₃)alkyl.
 3. The compound, tautomeror pharmaceutically acceptable salt according to claim 1, wherein X isO.
 4. The compound, tautomer or pharmaceutically acceptable saltaccording to claim 1, wherein X is NR₈, and R₈ is selected from thegroup consisting of hydrogen and (C₁₋₃)alkyl.
 5. The compound, tautomeror pharmaceutically acceptable salt according to claim 1, wherein L₁ is—CH₂—.
 6. The compound, tautomer or pharmaceutically acceptable saltaccording to claim 1, wherein R₁ has the formula:

wherein λ is selected from the group consisting of 0, 1 and 2; R₂₃ isselected from the group consisting of (C₁₋₃)alkyl and (C₃₋₆)cycloalkyl;and each R₂₆ is independently selected from the group consisting ofhydrogen, halo, (C₁₋₃)alkyl and (C₁₋₃)alkoxy.
 7. The compound, tautomeror pharmaceutically acceptable salt according to claim 1, wherein R₂ isselected from the group consisting of hydrogen, halo, and (C₁₋₃)alkyl.8. The compound, tautomer or pharmaceutically acceptable salt accordingto claim 1, wherein R₆ and R₇ are each independently selected from thegroup consisting of hydrogen and (C₁₋₃)alkyl.
 9. The compound, tautomeror pharmaceutically acceptable salt according to claim 1, wherein R₆ ishydrogen.
 10. The compound, tautomer or pharmaceutically acceptable saltaccording to claim 1, wherein R₁₃ is selected from:

R₂₁ and R₂₂ are selected from phenyl and pyridinyl, each optionallysubstituted with one or more substituents independently selected fromhalo, nitro, cyano, amino, hydroxy, (C₁₋₁₀)alkoxy, carbonyl, sulfonyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₄₋₁₂)aryl, andhetero(C₁₋₁₀)aryl; the optional carbonyl substituent is substituted withhydrogen, hydroxy, (C₁₋₁₀)alkoxy, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₁₋₁₀)alkylamino or amino optionallysubstituted with (C₁₋₁₂)cycloalkyl; the optional sulfonyl substituent issubstituted with (C₁₋₁₀)alkyl or (C₁₋₁₀)alkylamino; the optional(C₃₋₁₂)cycloalkyl and hetero(C₃₋₁₂)cycloalkyl substituents are eachoptionally substituted with one or more substituents independentlyselected from cyano, oxo, hydroxy, (C₁₋₁₀)alkoxy, amino, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, andhetero(C₃₋₁₂)cycloalkyl; and the optional (C₄₋₁₂)aryl andhetero(C₁₋₁₀)aryl substituents are each optionally substituted with oneor more substituents independently selected from halo, nitro, cyano,amino, hydroxy, (C₁₋₁₀)alkoxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, and (C₁₋₁₀)azaalkyl.
 11. The compound, tautomer orpharmaceutically acceptable salt according to claim 10, wherein R₁₃ is

each R₂₈ is selected from the group consisting of hydrogen, halo, and(C₁₋₃) alkyl.
 12. The compound, tautomer or pharmaceutically acceptablesalt according to claim 10, wherein R₂₁ or R₂₂ has the formula:

wherein λ is selected from the group consisting of 0, 1, 2, 3 and 4;each R₂₆ is independently selected from the group consisting ofhydrogen, halo, nitro, cyano, hydroxy, amino, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl,and (C₁₋₁₀)oxoalkyl; and R₂₇ is selected from the group consisting ofhydrogen, halo, nitro, cyano, hydroxy, (C₁₋₁₀)alkoxy, carbonyl, amino,sulfonyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₄₋₁₂)aryl, and hetero(C₄₋₁₀)aryl; wherein the (C₃₋₁₂)cycloalkyl andhetero(C₃₋₁₂)cycloalkyl substituents are each optionally substitutedwith one or more substituents independently selected from cyano, oxo,hydroxy, (C₁₋₁₀)alkoxy, amino, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, and hetero(C₃₋₁₂)cycloalkyl; the(C₄₋₁₂)aryl and hetero(C₁₋₁₀)aryl substituents are each optionallysubstituted with one or more substituents independently selected fromhalo, nitro, cyano, amino, hydroxy, (C₁₋₁₀)alkoxy, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, and (C₁₋₁₀)azaalkyl; the carbonylsubstituent is substituted with hydrogen, hydroxy, (C₁₋₁₀)alkoxy,(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₁₋₁₀)alkylamino or amino optionally substituted with(C₃₋₁₂)cycloalkyl; and the sulfonyl substituent is substituted with(C₁₋₁₀)alkyl or (C₁₋₁₀)alkylamino.
 13. The compound, tautomer orpharmaceutically acceptable salt according to claim 12, wherein R₂₁ orR₂₂ is selected from:

wherein R₂₃ is selected from the group consisting of hydrogen,(C₁₋₁₀)alkyl, and (C₃₋₁₂)cycloalkyl; R_(26a) and R_(26b) are eachindependently selected from the group consisting of halo, nitro, cyano,hydroxy, amino, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, and (C₁₋₁₀)oxoalkyl.
 14. The compound,tautomer or pharmaceutically acceptable salt according to claim 13,wherein R₂₃ is selected from hydrogen, (C₁₋₃)alkyl, and(C₃₋₆)cycloalkyl; R_(26a) and R_(26b) are each independently selectedfrom hydrogen, halo, (C₁₋₃) alkyl and (C₁₋₃)alkoxy; and R₂₇ is—CO—NH—R₂₃.
 15. The compound according to claim 1, which is selectedfrom:3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one;3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one;3-((4-(4-chlorophenyl)piperidin-1-yl)methyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one;(R)-6-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinonitrile;(R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile;(R)-3-((4-(4-chlorophenyl)-5,6-dihydropyridin-1(2H)-yl)methyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one;(R)-N-ethyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide;(R)-ethyl4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate;(R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoicacid;3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-6(5H)-one;(R)-N-methyl-4-(4((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide;(R)-N-cyclopropyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide;6-(4-((6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinonitrile;4((S)-3-methyl-4-(((R)-6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzonitrile;(R)-N-ethyl-3-fluoro-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide;(R)-3-chloro-N-ethyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide;(R)-3-chloro-N-methyl-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide;stereoisomers of any of the aforementioned compounds; tautomers of anyof the aforementioned compounds or stereoisomers; and a pharmaceuticallyacceptable salt of any of the aforementioned compounds, stereoisomers ortautomers.
 16. A pharmaceutical composition comprising: a compound,tautomer or pharmaceutically acceptable salt as defined in claim 1; anda pharmaceutically acceptable excipient.